Five years after the retirement of Agent K and the defeat of Edgar the Bug from ''Men in Black'', the secret New York City-based agency that monitors and regulates extraterrestrial life residing on Earth, Agent J–K's former partner and hand-picked replacement–is called to investigate the murder of an alien, Ben, at his pizzeria. The waitress, Laura Vasquez, tells him that the murderers are Serleena, a shapeshifting, plant-like Kylothian who has taken the form of a lingerie model, and her two-headed servant Scrad. Laura says they were looking for something called the Light of Zartha. J is strongly attracted to Laura, and in violation of MiB rules, does not Neuralyzer her to erase her memories.

Following a ghost invasion of Manhattan, paranormal enthusiasts Erin Gilbert and Abby Yates, nuclear engineer Jillian Holtzmann, and subway worker Patty Tolan band together to stop the otherworldly threat.

Two English comic book geeks traveling across the U.S. encounter an alien outside Area 51.