In Devil May Cry 2, the player guides either Dante or Lucia through an urban environment, fighting groups of monsters in fast-paced combat. The game consists of missions with specific goals in the play area of the game itself. The player's performance in each mission is ranked from D to S based on the time taken to complete the mission, the amount of Red Orbs collected, the overall "style" displayed during fights, item usage, and damage taken. In contrast to the rest of the gameplay, the style judging system used in the game has been cited as being the harshest in terms of how it judges the player's performance.
Combat itself is based on the "style" the player demonstrates during a fight. The rating the player gains for style is improved by hitting enemies continuously while avoiding damage. This ranges from "Don't Worry", progressing to "Come On!", "Bingo", "Are You Ready?" and peaking at "Showtime". If the character takes damage, the style rating falls back to "Don't Worry".
The game's controls convert short sequences of button presses into complex on-screen actions. New to the series is an evasion button, which allows Dante or Lucia to roll, dodge enemy attacks, or run along walls. Another new feature is a weapon-change button, which allows the player to cycle through ranged weapons without switching to the inventory screen.
The game also features puzzle-solving and exploration elements. Gameplay involves the player examining their surroundings to find items and orbs. Red Orbs are used to acquire new combat powers and abilities for the characters. These Red Orbs are "the blood of demons"; enemies drop them when they are defeated. Dante and Lucia can also purchase items, which allow them to restore their damaged health or even instantly revive should they be killed by an enemy's attack.
The Devil Trigger ability enables Dante and Lucia to transform into a demon form. This changes their appearance, increases their strength and defense, slowly restores health, and enables them to use special attacks and other passive and movement abilities, including increased speed and the power to fly. The Devil Trigger state lasts as long as there is power in the Devil Trigger Gauge, which increases by attacking or taunting enemies in the normal state and decreases by attacking in the Devil Trigger state or using Devil Trigger-only attacks. Unique to this game is the Desperation Devil Trigger — an enhanced form of the Devil Trigger — available to Dante when he is low on health.
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 is using demonic power in an effort 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 the demon Argosax.
Lucia eventually confronts Arius, who reveals that she was his creation. When she moves to strike him, 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 persuades her to rejoin the fight against Arius. Dante arrives at the tower to find Arius in the middle of his immortality-inducing ritual. However, Dante is not worried as he switched one of the Arcana with a false coin. 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 the partially summoned 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, and Lucia goes on to defeat him. Within the portal, Dante fights and defeats Argosax. Finding the portal closed behind him, 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. The player is not shown if Dante has returned.