In 2002, five years after the first Men in Black, Agent J is now the top operative for the MIB, the self-funded New York City-based agency that secretly monitors and regulates extraterrestrials' activity on Earth. J has no permanent partner since his trainer-mentor K resigned, and Agent L (from the first film) returned to work in a morgue. Subsequent partners have not lived up to the standards of K or J.

While investigating a seemingly routine crime at a SoHo pizzeria, J uncovers a diabolical plot by Serleena, the shapeshifting Kylothian Queen. After destroying several planets, she sneaks onto Earth, and disguises herself as a lingerie model. In her own form, she resembles a plant-like hydra. The memory-wiped "neuralyzed" Agent K has resumed civilian life as Kevin Brown, postmaster in Truro, Massachusetts. The post office is full of alien workers, so K feels right at home. To stop evil Serleena, J must convince Kevin to rejoin MIB. K is the only operative still alive who knows how to find the Light of Zartha. The planets that Serleena destroyed were where she looked unsuccessfully for the Light. J must now work to restore K's memory and have him rejoin the Men in Black.