Dante is the child of an angel named and the demon, and seemingly hunts down other demons in the twisted shadows of Limbo City, while slowly coming to grips with his ethereal powers. Dante grew up in various institutions, orphanages, youth correction facilities, and foster homes, but these were mostly operated by demons, and often resulted in torture and violence. Dante has therefore developed a deep hatred of demons and authority in general, but tries to stay incognito.
In spite of this he attracts attention thanks to his violent tendencies and the actions of the demons against him. Dante is not subtle in his war against them, even going so far as punching out a bouncer in front of a group of people in order to enter a nightclub run by demons. The demons are even less subtle when fighting Dante, perfectly willing to tear apart Limbo City to subdue him. These mutual acts of sabotage have allowed the demons to use the media to portray Dante as public enemy number one.
One night, after having a wild time at Devil's Dalliance, Dante was careless and allowed a Hunter to track him. At his trailer, he is woken up by Kat, who warns him that he's being followed. Suddenly, the Hunter appears and pulls Dante into Limbo. As it destroys his trailer, Dante quickly puts on his clothes and finds himself surrounded by demons. Defeating them, he encounters Kat again, who explains that she's a psychic and can see him, even though she's in the real world, and she wants to help him. Dante initially turns down her offer, but Kat warns him that he shouldn't fight the Hunter. Following Kat to the rift, Dante fends off against the Hunter's attacks, including the rip-off of the Ferris wheel. He tries to use Ebony & Ivory, but Kat informs him that it's bulletproof. After she throws a Wiccan-charmed bottle at its face and weakens it, Dante fights and defeats the Hunter. With its dying breaths, it calls him the Son of Sparda and tells him that he is dead just like his mother, the “whore”. Dante replies that he doesn't know who his mother was, but the Hunter wasn't the first to call him a son of a bitch. He then kills the demon and returns to the real world, with the pier heavily destroyed due to the battle in Limbo. Holding his pendant, Dante thinks of Eva, whom he barely remembers. As he leaves the pier, Kat finds him again, informing him that her boss knows him and wants to meet him. Although resisting at first, he eventually accepts and Kat drives him into Limbo City. She reveals to Dante that she's part of the Order, and the man in the mask that frequently appears on the news is her boss.
Arriving at the entrance of the Order, Dante comments that it wasn't what he expected because it looks like a small garage, and Kat replies that was the idea, since the real entrance is well hidden. As they enter, she goes on and tells him that the demons are enslaving mankind, and the Order is fighting against them as the last line of defense. Then they enter a room, where a man dressed in black was waiting for them. Seeing that Dante doesn't recognize him, the man reveals himself to be Vergil, his long lost twin brother and the establisher of the Order. Vergil asks Dante to join with him in fighting the demons and saving mankind. But Dante declines, stating that he's the loner type. Stating that leaving will be a mistake, Vergil asks Dante to give him a chance to show the truth about who he is.
Dante is then brought to Paradise, Dante and Vergil's home which has been long abandoned. There, Kat opens a gateway, allowing Dante to enter Limbo and find out about his past. While exploring the mansion, he comes across a torn portrait of his father Sparda with a winged carving at the base engulfed with a demonic aura. Upon touching it, Dante gains the Arbiter. As he regains his childhood memories, he stumbles across an insignia which resembles the tattoo on his back. He is suddenly transported into another dimension, where he finds a large stone statue that is chained down. Dante gains the demonic form of the Ophion and breaks one of the chains. When he returns to Limbo, he finds another portrait, this time of his mother Eva, with a winged carving, shining with an angelic blue. As he touches the carving, Dante obtains Osiris. Continuing his search, Dante finds a blue rose, which takes him back to the dimension from before. He gains the angelic form of the Ophion and breaks another chain. Later, Dante finds a picture of Sparda, Eva, Vergil and himself. He suddenly remembers everything. Eva gave him his pendant when he was a child, and he would have spars with Vergil, often winning them easily. They were a family, until Mundus and his demon army found them. He broke into the mansion and killed Eva, ripping her heart out right in front of Dante's eyes. Sparda quickly took his sons and escaped, erasing their memories and separating them. He hid them among the humans to keep them safe from Mundus. Returning to the real world, Dante confirms with Vergil that they are indeed twin brothers, the latter showing his blue pendant that Eva gave to him. Vergil informs Dante that their father Sparda has been eternally banished, condemned to a fate far worse than death. Dante tells Vergil that he wants to know more, and they, along with Kat, leave the mansion.
Dante and Vergil then travel to an old playground, where Eva used to take them to as children. It is here that Vergil reveals everything. Over 9000 years ago, Mundus became the supreme ruler of the demons with the help of Sparda, his most trusted lieutenant. But Sparda betrayed Mundus and fell in love with an angel, Eva. They union gave to a new kind of life: Nephilim, half-demon, half-angel hybrids. When Mundus learned of Sparda's betrayal, he became so furious and hunted the lovers down. He killed Eva and sentenced Sparda to endless punishment and pain. But the lovers knew that Mundus will soon be defeated by their sons, because only a Nephilim can kill a demon king. Also, Mundus believes that there's only one Nephilim, never learning of the other. To ensure that his sons can fight the demon king, Sparda gave the Rebellion to Dante and the to Vergil.
Their conversation is interrupted when a Looker finds them, dragging Dante into Limbo. After fighting off a horde of demons, Dante tries to reunite with Kat, but the Limbo dimension separates them, creating a large space of distance. As he searches for another route, Dante finds another blue rose, which takes him back to the same dimension like before. This time, he learns how to glide when he jumps, allowing him to reach farther distances. Breaking another chain, Dante returns to Limbo and heads to Kat and the gate, making it safely to the real world.
Back at the Order's hideout, Vergil shows Dante that Mundus rules the real world in his human guise, Kyle Ryder, CEO of Silver Sacks Tower. As a banker, Mundus controls everything through debt, making him superior over humans. He keeps the humans monitored with the Raptor News Network, and he makes them docile with the Virility soft drink. Mundus draws his powers through the Hell Gate, and is immortal when connected to it. Vergil plans to draw Mundus away from the gate by getting his attention, giving the brothers a chance to kill him. To make him notice, their strategy is to take down his soft drink plant and news corporation.
Picking Virility as their first target, Dante and Kat head for the plant. Along the way, Dante knocks out a can from a man's hand, which catches the attention of a demonic camera. It pulls Dante into Limbo, but he quickly dispatches it. However he and Kat quickly discover that there are more demonic cameras throughout the city, and Limbo itself is trying to trap and kill him. While Kat leaves to avoid the cops, Dante destroys the cameras and avoids Limbo's traps. As he reunites with Kat at Saint Agares's Church, Limbo erupts into all out chaos. Dante quickly makes his way to her gateway marked on the glass window, shattering it into pieces as he escapes Limbo.
As they enter the Virility factory, Kat informs Dante that he needs to destroy the secret ingredient of the drink: an ancient succubus named Poison that lies deep within the facility. Since the only way of reaching Poison is through Limbo, Dante and Kat head for the rift located in the storage room. After Dante enters Limbo, Kat instructs him to retrace his steps back to the mixing room and meet her there. When he reaches the room, he finds grotesque tubes feeding into the mixing tanks that people sampled cups of Virility from in the real world. Reaching the air duct, Dante travels down the tunnel with the help of Kat's “egg-timer.” Going on his own, he finds Poison who calls him the Son of Sparda and Eva the “whore.” After they shouted cusses at each other, Dante battles and defeats the succubus by cutting the lines that held her, causing her to fall into the rancid waters. But as he makes his way out, she resurfaces and battles him again. Dante fights back and causes Poison to fall with the current towards the stirring rotors. As she tries to cling on, he breaks her grip and she is caught within the rotors, sliced up into pieces by the blades. With Poison's death, Dante obtains the Eryx gauntlets.
With their sights now on the Raptor News Network, Dante and Kat head to meet up with Vergil. While she is driving, Dante asks why she's so close to his brother, saying that he wants to know her reasons why she's helping Vergil. He states his appreciation for her help, even though he didn't ask for it, and he wants her to trust him since he trusts her. After learning of Kat's horrific pasts, Dante promises that he'll stick with her and his brother to the end. They reunite with Vergil at a city bridge, where they can clearly see the Raptor News Tower. To destroy the network, Dante must take out the demon that is running it: Bob Barbas. With Kat's glyph on the bridge, Dante falls through and enters Limbo, which is not the river but an upside-down realm. He discovers that the network tower is disguised as a reflection on the river in the human world, commenting that he understands why Bob's point of view is “so upside down.” As he heads for the tower, Dante discovers Bob's penitentiary, which is filled with human souls that are tortured cruelly. Later on, his path is obstructed when the train rails he is walking on is destroyed. He then spots a blind old demon, Phineas, helplessly fighting off harpies. After learning of Dante's intentions of killing Bob, the prophet offers his help in return for a favor: the retrieval of his cybernetic right eye. As Phineas calls for the harpies and distracts them, Dante heads for their nest, where the eye is located. After he obtains the eye, he fights and kills the harpies that surrounded him and later returns to Phineas. Dante keeps up his end of their deal and gives the prophet his eye. When Phineas' vision is returned, he sees Dante and recognizes him as Sparda's son and a Nephilim. With his part done, Dante is led by Phineas to the Raptor News Tower.
Along the way, Dante is brought to a statue containing the soul of Assiel, who was a Nephilim just like him. Phineas tells him that there were other Nephilim before, but they were hunted down and killed because of their formidable powers and great potential. For Dante to reach his own potential, Phineas suggests for him to go to Assiel, who may hold the key. When Dante approaches Assiel, she recognizes him as one of her own kind and shows him an emblem. As he grabs it, he is transported into the other dimension. When Dante breaks the final chain, his pendant begins to glow and the statue begins to move. As it opens its arms, the mirror at its chest glows brightly, and Dante sees a message left by his own mother. Eva apologizes to him for not being able to protect him. She tells him that she's giving him a choice that she and Sparda never gave to him: a great power to forge his own path. That power is freedom. Eva tells Dante to be brave and that she loves him. Dante's Devil Trigger is then unleashed, granting him power that is greater than anything he had before. When he returns to Limbo, Phineas comments that he's found his inner devil, but has not reached his full potential yet. Dante replies that he just wants to kill Mundus, but the prophet asks who will take the demon king's place, leaving the Nephilim utterly confused.
Reaching the tower, Phineas says that he cannot go further because he cannot fight anymore, but Dante thanks him regardless. The prophet states that he helped because he believes that Dante may stand a chance against Mundus. His faith in the Nephilim was strengthened because he saw not only Sparda, but Eva as well in him. Dante learns from Phineas that Mundus has one weakness: his mistress, Lilith, is bearing his child. Nothing will hurt Mundus more than their deaths, since the child is his heir. But the prophet warns Dante that the fury of the demon king is boundless and thousands might perish. After Phineas prepares the way one last time, he disappears, and Dante continues on his own. As he gets closer to the tower, a giant beam shoots out, hindering his path, and he realizes that he has Bob's attention. Entering the tower, Dante discovers Bob in his demonic form and battles him, punching him with “hard hitting news.” In the midst of the fight, Bob reports that SWAT teams have begun raiding The Order's hideout, targeting Vergil and Kat. With his anger raging, Dante defeats Bob and shoots his human form, killing him. As Dante returns to the human world, he gains the Aquila blades.
Rushing back to the hideout, Dante finds that the SWAT teams have not found a way inside the hideout yet, prompting him to hurry and find Kat and Vergil. A Looker, disguised as a SWAT member, spots Dante and pulls him into Limbo, making him unable to save the members of the Order as they are shot and killed by SWAT. However he finds Kat, who is terrified and confused but safe. She tells him that Vergil is in the Octagon room, trapped in Limbo. They hurry to Vergil, with Dante helping Kat avoid capture. As they reach the Octagon, Dante saves Vergil by killing the Butcher that was cornering him. He then rushes for them to leave, but Vergil refuses, as he is trying to destroy reliable data and their plans so he can prevent SWAT from getting their hands on them. Kat proceeds to activate the self-destruct, as it can only be done in the real world. Having no other choice, Dante fends off against the onslaught of demons, receiving the Revenant shotgun from Vergil. As Kat and Vergil finish, SWAT has almost broken through. Dante refuses to leave Kat behind, but she and Vergil tell him that she cannot escape. Telling his brother to go on ahead, Dante tells Kat not to fight back and he promises that he'll come back for her. He watches in despair as two SWAT members shoot Kat in the shoulder, beat her mercilessly and drag her unconscious body away by her legs. Dante quickly catches up with Vergil and they exit Limbo, leaving the hideout behind as it is destroyed.
Later, they receive a video message from Mundus, who tells Vergil to trade Dante in for Kat. As Vergil refuses to take a high risk and rescue Kat, Dante insist that they save her, but use Lilith as the trade since she bears Mundus' child. Vergil eventually agrees, although he still thinks that it is a waste to save Kat. After learning that Lilith is the owner of Devil's Dalliance, Dante heads for the nightclub. He knocks out the bartender with an uppercut and goes inside with no problem, avoiding one of his ex-lovers. After Dante is spotted by a Looker, a spotlight is placed on him, and Lilith drags him into Limbo. As he states that he's after her, Lilith forces him into playing “The Devil has Talent” game show. He must pass all of the levels to get an audience with her so she can kill him, but if he fails, then both he and Kat will die. When Dante passes all of the levels, and he battles Lilith and her child. Defeating them, he points Rebellion at Lilith, promising that he'll spare her and the child if she does exactly as she says. As she quickly submits, Dante brings her with him. He then has Vergil send a video message to Mundus, stating his counter proposal for the trade: Kat's life for the life of the child.
Dante and Vergil set up the trade at the shipping docks. They release Lilith as a SWAT team comes and gives Kat. The trade goes well until Vergil shoots and kills Lilith and the child. As both sides begin shooting at each other, Dante hurries to save Kat while Vergil kills the SWAT team. Suddenly, the three of them are sucked into Limbo by Mundus, who is horrified with the death of his heir. Dante hurries through the chaotic dimension and protects Vergil and Kat from large debris that gets into their car's path.
Getting back to the safe house, Dante and Vergil learn from Kat that since Mundus is weakened from his last outburst, this is their chance to kill him. After she shows them a map of Silver Sacks Tower, they go and make their last stand against the demon king. Dante storms through the front doors of the tower and gets Mundus' attention while Vergil sneaks inside from the back to get to the security room undetected. Dragged into Limbo by the demon king, Dante fights his way through the tower as his brother helps him by overriding the security. During one of their brief reunions, Dante receives the Kablooey firearm from Vergil. Breaking into the main core of the tower, he makes his way through the Furnace of Souls and returns to his brother one last time, going together for the final showdown with the demon king. However, the vault to Mundus's office is suddenly closed, forcing Dante and Vergil to reactivate the four generators that power the vault. Once it opens, Dante goes in alone to draw Mundus out, while Vergil waits for the right moment to sneak inside and close the Hell Gate.
As Dante finally confronts Mundus face to face, the demon king asks him why he killed the child. The Nephilim replies that he did it for the freedom of mankind, but Mundus questions his answer, explaining that humans misuse their freedom on each other with violence and war. Dante then changes his answer, saying that he killed Mundus' child to avenge Eva's death. He taunts the demon king, saying how priceless it was watching the child die. Suddenly, Dante is blasted out of the office by Mundus, who then rushes and grabs him as they zoom out of the tower. On top of another building, he is pinned down as Mundus digs his fingers into the Nephilim's chest for his heart. Unable to fight back, Dante slowly loses his conscience as his mother's murder flashes through his eyes. But Vergil successfully closes the Hell Gate and saves Dante, stabbing the now mortal Mundus. Dante then pushes the demon king off the roof, spitting on him as he falls on a car below. However, Mundus rises up as his true form and battles the brothers. Dante keeps Mundus distracted while Vergil opens the third eye. But when Mundus overpowers Vergil, Dante unleashes his Devil Trigger and stops the demon king, allowing Vergil to projectile a sword and open the eye. Taking the opportunity, Dante pulls out Mundus' eye with Ophion and severely punches him in the face with Eryx. But the demon king pulls Dante off his face and slams him into a nearby building, deactivating his Devil Trigger and rendering him unconscious. As Dante falls, Vergil quickly teleports and saves him, landing safely inside. Looking back, they see that Mundus is showing cracks, and his true body is at the core. But as Mundus attacks them again, Vergil is sucked into the core, pulled in and attacked by the demon's true body. Meanwhile, Dante fights Mundus, destroying his arms and severing his eyes. With the outer shell weakened, Dante rushes inside and slices Mundus' true body. He then grabs Vergil and escapes as the demon king explodes.
Reuniting with Kat, the three of them look out from the old playground at what's happened to the city, since Limbo has collapsed into the real world. As Dante claims that the humans are now free, but Vergil shows his true colors, stating that they can now rule mankind. He explains that his plan is for him and Dante to rule the humans together. Dante then realizes that all this time, they were fighting for Vergil's freedom from Mundus so he can rule himself. Vergil claims that humans are frail and helpless and they, the Nephilim, saved them from Mundus. But Dante disapproves, saying that if it wasn't for Kat, a human, then they wouldn't have defeated Mundus. Refusing to stand aside and let Vergil take the demon king's place, Dante draws Rebellion and battles Vergil. As the fight rages on, the brothers release their Devil Triggers, unleashing their full powers on each other. But in the end, Dante stabs Vergil at the heart, pinning him down. As he drives Rebellion deeper, Kat pleads for him to stop, begging him to have mercy on Vergil, so Dante relents, withdrawing his Rebellion. Helping Vergil to his feet, Dante states that the world is under his protection, but Vergil scoffs that Dante's chosen the wrong side and will never be human. Dante and Kat glumly watch as Vergil uses the Yamato to open a rift, then rebukes Dante for spurning his brother. Dante, unsure of who he is anymore, is reassured by Kat that he is himself, nothing more nor less, as Dante's eyes begin to glow a demonic red.