The novel begins with Dante, under the alias Tony Redgrave, confronted by the thug "Mad Dog" Denvers for the ninety-ninth time. Dante kills all of Denvers' men and leaves. As Denvers reminisces about how Dante's appearance two years previously caused the fall of the local underworld, he is killed by scythe-wielding devils screaming Dante's name.
Nell examines a gun while chatting with Dante
In Bobby's Cellar, a mercenary hideout, Dante talks with his partner Grue. He then leaves Bobby's Cellar, heading to Goldstein's Shop, run by gunsmith Nell Goldstein. Bantering with Nell, Dante mentions he wrecks guns quickly due to the rate of fire he employs. Returning to Bobby's Cellar, Dante acquires a lucrative job with Grue. During the job it becomes clear to Dante and Grue that it's too dangerous, so they retreat. Later, as both men evaluate the aftermath of the pitched battle, they are attacked by the corpses. Dante destroys them, though Grue freezes. Afterwards, Grue and Dante eat dinner with Grue's family.
At Bobby's Cellar Enzo introduces a new mercenary named Gilver, a tall man swathed in bandages who wields a katana. Gilver fights Dante, proving himself equal. Deciding to settle the fight with drinking, Dante wins and Gilver is robbed by the bar patrons. After leaving, Dante is beset by demons and an undead Denvers. Dante awakens in the home of a local woman, who he spurns before leaving. He learns that killing Denvers has lead to a bounty being placed on his head by the Oz Club. He leaves to confront the club directly. Entering a bank, he fights the same demons once again. Defeating them he runs into Gilver, who has slaughtered the Oz Club.
Dante and Gilver fighting with their swords
Weeks later, Dante and Gilver are now being paired on numerous jobs and Grue is missing. On the way to work, Dante stops by Nell's home, giving him two pistols and warning him about Gilver. Dante runs into Grue, who has been taking assassination jobs. After leaving Dante, Grue kills a heavily in debt thug. This sparks a demonic transformation among the thug's friends and Grue's hiding place is revealed by Gilver. Grue ignites a grenade on his chest, trying to kill Gilver. Dante and Gilver continue as partners, and Enzo reveals that Grue did assassinations because of his daughter Jessica's illness. Dante goes to the hospital and finds it overrun by demons. Dante faces the demon in charge, who is feeding on Jessica's despair. He kills the demon and Jessica, shattering the connection between the human world and demon realm.
Due to the hospital massacre and Grue's disappearance, Dante is publicly scorned by other mercenaries. Gilver converts the patrons of Bobby's Cellar into demons while Dante goes to Nell Goldstein's for rest. Soon after he leaves, an explosion engulfs Goldstein's Shop in flames. Dante charges in, finding Nell working on two pistols made especially for him: Ebony and Ivory. Giving him the pistols, Nell dies. Dante ceases using the Tony Redgrave alias. Dante returns to Bobby's Cellar and confronts Gilver. Amidst a furious sword fight, Gilver shoots Dante with the shotgun purchased at Nell's shop. Fatally shooting Gilver in turn, Dante is horrified to discover that Gilver is his brother Vergil.
Much later, Enzo drops by Bobby's Cellar and helps Dante leave. In the novel's epilogue, Dante sits in his shop as Devil May Cry begins.