It turns out Elizabeth is a monster hunter and transforms Vargas into Belial, hoping to use the demon to destroy all monsters. Dylan and Marcus manage to distract Belial long enough for the vampires and werewolves to kill Elizabeth, thus breaking the spell and sending Belial back to Hell and saving the day. Dylan decides to return to his role as supernatural peacekeeper, and makes Marcus his partner.
One night, a woman named Elizabeth (Anita Briem) walks upstairs to find her father dead and mangled. She also sees a horrifying creature fleeing from the house. After the cops are unresponsive, she ends up calling a private investigator named Dylan Dog (Brandon Routh), whose card she received from her priest. Dylan and his assistant Marcus (Sam Huntington) arrive at the scene, but as soon as Anita alleges her father was killed by a monster, Dylan storms out claiming to have retired from that life.
Later that night, however, Marcus is killed by a supernatural assailant. This death prompts Dylan to take Elizabeth's case. It turns out that the city of New Orleans is populated with vampires, werewolves, and zombies. Dylan, a human, had been appointed as an independent peacekeeper to settle all disputes that arose between the monster sects. Most monsters simply wish to live out their lives in peace, and Dylan helped to ensure the peace. Unfortunately, Dylan's wife Cassandra was killed by vampires. In revenge, Dylan destroyed the vampire council and retired. He now has a reputation as a monster hunter and has remained emotionally unavailable ever since.
Elizabeth reveals that her father was in possession of the supernatural relic called the "Heart of Belial." Dylan's search leads him to confront Gabriel Cysnos, a leader of one of the werewolf sects and former friend of Dylan. Dylan is aided by Marcus, who is now a zombie (and a member of a zombie support group). Everyone tied to the Heart of Belial and the murder of Elizabeth's father is soon found dead, including Gabriel. Dylan also learns that the Heart can be used to summon a vampire-demon named Belial, who will be a slave to the person who reincarnates him. Further, Belial may only be killed if his master is also killed.
Eventually, Dylan discovers that someone has been controlling a giant, mutated zombie to kill everyone. He accuses new vampire leader Vargas (Taye Diggs) of controlling the zombie, but has no direct evidence. Dylan also grows closer to Marcus and begins a relationship with Elizabeth. Dylan and Marcus eventually finds the Heart of Belial, but the pair are soon captured by Vargas. While gloating, Vargas admits he killed Cassandra so that Dylan would take out the council and allow him to rise to power. It turns out the Cysnos clan actually was trying to protect the Heart from both Vargas and the monster hunters, but thanks to Dylan, they have failed. Vargas also states that he intends to use Elizabeth as the host for Belial. Vargas will then use Belial to establish himself as the ruler of all monsters.
Dylan and Marcus escape and run off to stop Vargas. It turns out, however, that Elizabeth is actually a monster hunter. She turns the tables and manages to use Vargas as the host of Belial. As Belial's master. Elizabeth to use Belial to destroy all monsters, regardless of their peaceful nature. Belial disobeys her orders and instead, intends to destroy the entire world. Dylan and Marcus try to stop Belial as Elizabeth flees. Before she can get too far though, Elizabeth is confronted by a group of vampires and werewolves led by Gabriel's son. They manage to kill Elizabeth, whose death breaks the spell and sends Belial back to hell.
Dylan is hailed as a hero by the monsters and he gives the Heart of Belial to Gabriel's son for safekeeping. Dylan decides to once again serve as the supernatural peacekeeper, and makes Marcus his full partner.