To investigate recent events, Credo gives Nero the task of stopping Dante and discovering his true intentions. However, the city suddenly finds itself under siege by a demonic attack, seemingly related to Dante's appearance. While Credo leads Kyrie and the townspeople to The Order of the Sword Headquarters, Nero embarks on his quest through the destroyed city to Fortuna Castle. At the castle Nero meets Gloria, an Order of the Sword member. As his quest deepens, Nero uncovers the secret lab of Order of the Sword Member Agnus, who has secretly been experimenting with demonic power by siphoning the intense demonic energy from the shards of Yamato (the sword that used to belong to Vergil, Dante's brother). Imbuing normal items such as swords and suits of armor, Agnus has secretly created an army of demon infused warriors and several Hell-Gates across Fortuna under the orders of Sanctus himself.
Shocked by the treachery of the Order, Nero fights Agnus but is mortally wounded by him. During the fight, Nero fully unlocks his demonic power and mends the broken Yamato. He destroys the lab and Agnus flees to inform Sanctus. As he searches for the Order, Nero contemplates his human and demonic nature. Fighting the creatures spawned from Agnus's Hell Gates, Nero discovers to his dismay that Credo is part of the conspiracy. The fight between Nero and Credo is interrupted by Agnus who brings Kyrie to see Nero transform into a devil, which makes her lose her faith in Nero. Agnus then kidnaps Kyrie and departs. Credo, stunned by The Order's blatant use of his sister, is shaken in his belief and apologizes to Nero, promising to return once he has investigated Sanctus's true intentions.
Nero decides to save Kyrie from Sanctus, but encounters Dante. Nero wishes to simply pass him, but Dante wants Yamato. A fight ensues. After the fight, Dante reveals that it was a test to make sure that he could trust Nero with the sword. They trade names and form a steady alliance as Nero continues forward.
Suddenly, Gloria appears before Dante as Nero leaves, and reveals that she is actually Dante's partner, Trish. (Trish was posing as Gloria for the entire game.) Finally, Nero finds Sanctus with an enormous statue, in Sparda's image, which he calls the Savior. Sanctus reveals that only Yamato and the sword Sparda, along with Sparda's blood can awaken the Savior and unleash hell. They battle and Sanctus uses Kyrie as a human shield to distract Nero and capture him. Suddenly Credo returns and attempts to rescue them. Unfortunately Credo is defeated by Sanctus who stabs him with Yamato, and later Nero. Revealing that Nero is a descendant of Sparda's blood, The Savior awakens and Nero is absorbed into it while Nero promises to Kyrie he will free them. Dante and Trish appear and promise Credo in his final moments to save Kyrie and Nero.
Under the city, Agnus opens the hell gate with Yamato which releases countless demons upon the city. Using The Savior to defeat the oncoming demons, Sanctus enacts his ultimate plan. Dante, making his way through Fortuna, succeeds in destroying all the hell gates and kills Agnus, sealing the final hell gate. Finally taking on The Savior, Dante takes Yamato and drives it through the Savior's chest, where Nero reclaims it inside. Facing Sanctus, Nero gains the upper hand in the battle. Nero defeats him and frees Kyrie in the process.
In the aftermath, Nero and Kyrie escape the confines of The Savior and Nero returns the Sparda sword to Dante. Destroying the final demon, Nero makes peace with his demonic heritage (for the time being) after acknowledging the power it has given him to save those he cares about. As Nero sees Dante off, Dante decides to entrust Yamato with Nero. This heavily implies Nero is the rebirth of sparda as a human but still the demonic powers are inside him. Nero and Kyrie reconcile in the ruins of Fortuna. They are finally about to share a kiss when they are interrupted by scarecrow demons. Nero, finally embracing his demonic powers, readily goes to face them off.
Meanwhile, Lady returns to the Devil May Cry office where she had hired Dante to go to Fortuna to combat the Order of the Sword in the beginning. Although the job is complete, Lady offers a menial reward, citing that Dante and Trish's presence escalated the simple job she had hired them for into the situation it became. Trish and Lady argue over the reward money but Dante reluctantly accepts it. A phone call interrupts and Lady exits the shop. Trish answers and reveals that the caller is offering a job, which Dante happily accepts.
