Edgar and Alan Frog interrupt a half-vampire Senator who is killing a Congressman to finish his transformation into a full-vampire, but in the ensuing chaos Alan is forced to drink vampire blood, which will transform him into a half-vampire himself.
Five years later in San Cazador, California, Edgar is facing eviction from his trailer and tries to raise funds by selling his collection of old comic books to his friend Zoe, who works at a local comics shop. While there, a famous blogger named Johnny Trash enters; Zoe explains that Johnny is there for a rave that's going on in the town.
Back at his trailer, Edgar is approached by Gwen Lieber, a writer of romantic vampire novels, whose brother Peter was kidnapped during a rave in Ibiza, Spain, and she suspects vampiric activity. She gives him a vial of a drug called "The Thirst" which is given to people at raves hosted by a person known as "DJ X"; he determines that it is vampire blood. Gwen offers him a large sum of money to rescue her brother, but he turns it down.
DJ X and his associates are transporting Peter - bound and drugged - in a small plane. DJ X and three others jump from the plane in flight, landing safely to meet Johnny Trash for a live interview. DJ X kills Johnny afterward, since the blogger had served his purpose in promoting the rave online.
Edgar visits Alan, who is now half vampire and satisfies his thirst for blood by feeding on animal blood acquired in his job as a taxidermist. Edgar tries to enlist Alan's aid in stopping DJ X from raising an army through his raves, but he refuses, having lost all hope that he can be saved and believing that the whole Alpha Vampire theory is just a "neverending pyramid scheme".
Remembering his youthful days with Alan and Sam Emerson, Edgar resolves to take the job alone but Gwen introduces him to Lars Van Goetz, a former reality-TV star hoping to use the mission to make him famous again; Edgar reluctantly accepts his help.
After a visit to Sam's grave (who Edgar had been forced to kill in self defense after Sam was turned into a vampire), in which Edgar returns to Sam the Batman #14 that Sam had boasted having when they met, Edgar finds that Alan has left him a book of vampire history to help in his mission. Edgar gives the book to Zoe to research. She is attacked by a vampire, but she and Edgar defeat it, and she explains what she has learned about a ritual sacrifice during a Blood Moon, such as the one that will occur the night of the rave.
Congressman Blake, now Edgar's weapons designer (for a fee) outfits Edgar and Zoe for battle. After fighting off an attack on Blake's house, they meet up with Gwen, Lars, and Claus, and set off for the island where the rave is taking place. Leaving Gwen behind for her safety, the remaining four go inside in search of Peter. Lars finds him, but thinking that the whole thing is staged, leaves Peter to rescue him at a more dramatic time. As they fight various vampires, Lars gets killed, Edgar is injured, but rejoins Gwen, Claus, and Zoe in returning to the building.
DJ X is distributing The Thirst to the crowd, and preparing to sacrifice Peter. Edgar takes on DJ X, and is narrowly saved by the timely arrival of Alan. The vampire hunters rally, and Edgar impales DJ X with a resin spike grenade (a weapon stolen from Area 51 by Congressman Blake) before he and Alan finish him off with swords through the heart.
To their surprise, the death of DJ X doesn't cause the half-vampires to revert. They discover that Peter was the real alpha vampire (and Gwen is not his sister), whose power DJ X was attempting to extract. Gwen's rescue mission was also a ruse to bring Edgar to Peter, who wanted him to become his personal vampire hit-man, to keep other vampires under control. Peter kills Gwen instead of turning her like she wanted and orders the other vampires to kill Edgar and the rest. Peter attempts to use his partial control over Alan against Edgar, but Edgar douses Peter with water which he simultaneously blesses into holy water, destroying Peter and returning the others to normal.
Later, as Alan enjoys getting his first suntan in years, Zoe and Edgar reflect on their adventure. Edgar wonders about her knowledge that vampires were real, which she dismisses as "a hunch". Edgar comments about something he's just read about female werewolves being able to transform at any time, and the audience is teased with the sight of her eyes becoming wolflike.
