Following the events of Devil May Cry 4, Nero is working as a demon hunter for Dante's Devil May Cry agency along with his friend, gunsmith Nico Goldstein. One afternoon, Nero is working at the agency when a hooded man enters. Nero offers the stranger food when he suddenly rips off his demonic Devil Bringer arm, along with the Yamato sword. Some time later, a mysterious man known as V hires Dante and his crew to take down a powerful demon named Urizen. The group travels to Red Grave City, where they find a demonic tree called Qliphoth planted in the city, killing people for their blood.
The gameplay features the return of Dante and Nero as playable characters, along with a new character, named V. The gameplay is similar to that of the other titles in the Devil May Cry series, focusing on fast-paced "stylish action"; The player fights off hordes of demons with a variety of attacks and weapons. They receive a style rating for combat based on several factors, such as move variety, the length of a combo, and dodging attacks. The game's music changes based on the player's performance in combat. Every time the player interacts with the mechanic Nico or finds a statue, they can buy new abilities for each character.