Devil May Cry 2 begins with Lucia and Dante separately entering a museum where an important item called the Medaglia is stored. After defeating a group of demons in the museum, Lucia invites Dante to follow her to the Dumary Island, where he is introduced to Matier, her mother. Matier explains that she once fought alongside Dante's father, Sparda, to defend the island against demons. She asks Dante to help fight Arius, an international businessman who uses demonic power and seeks to conquer the world. Dante flips a coin in answer, and decides to help when the coin lands on heads. After Dante leaves Matier and Lucia discuss the Arcana, the items required for Arius to raise Argosax.
Lucia eventually confronts Arius, who reveals that she was his creation. When Lucia moves to strike Arius, he uses his magic to blast her away. Shortly afterward, Dante meets up with Lucia, who gives him the last of the Arcana before leaving. Dante then encounters Matier and tries to pass the Arcana to her. Matier, in turn, asks Dante to take the Arcana to save Lucia, who has gone to fight Arius again. Dante flips the coin again to decide if he will help; it lands on heads, and he departs to aid Lucia. Meanwhile, Lucia enters the Uroboros tower and attacks Arius, who captures her. Dante arrives and trades the Arcana for Lucia, then attacks Arius. To escape, Arius forces Dante to decide between saving Lucia or killing him.
Lucia, worried about the ritual and conflicted about herself, wonders how they will stop Arius. Dante waves her off, stating he will find a way. Dante leaves Lucia to think as he departs to defeat Arius. Matier arrives a short time later, sets Lucia's mind at ease, and decides to rejoin the fight against Arius. Dante arrives to find Arius in the middle of his immortality-inducing ritual. Apparently not at all fazed by the completion of the ceremony, Dante stands confident. Another fight ensues, in which Dante finishes Arius off with his pistols. Outside, Lucia confronts Dante and demands that he kill her because she fears she will become a demon herself. Before the issue can be resolved, a large stream of energy strikes the tower and a portal to the demon world is opened. Dante and Lucia argue over who will enter and close it from the inside; Dante offers to leave the issue up to fate. He flips the coin and it once again lands on heads, leaving Dante to enter the portal to deal with Argosax after leaving the coin with Lucia.
After Dante departs, Arius returns to life bearing demonic power. While Lucia fights Arius, he finds himself injured and attempts to distract her, a tactic which fails; Lucia goes on to defeat him. Within the portal, Dante fights and defeats the partially summoned Argosax. Finding the portal closed, Dante instead drives further into the demon realm on a motorcycle. In the aftermath of the battle, Matier attempts to reassure Lucia about Dante's fate, insisting that Sparda returned from a similar trip. Lucia examines the coin Dante left with her and discovers that both sides are identical. Sometime later in Dante's shop, Lucia muses about Dante. Outside the sound of a motorcycle echoes, and Lucia leaves to investigate. It is left up to the player's interpretation if this is Dante or not.