Five years have passed since the events of Men in Black. Agent J, portrayed by Will Smith, has now risen to the top of the MIB ranks, spearheading the secretive New York City agency that monitors extraterrestrial activities on Earth. With his partner Agent L deciding to return to her previous life, J finds himself working solo, as his subsequent partners have failed to meet his high standards.
During the investigation of a seemingly trivial crime at a SoHo pizzeria, J stumbles upon a sinister conspiracy orchestrated by Serleena, a shape-shifting queen from Kyloth, who masquerades as a lingerie model. In her true form, she resembles a plant-like hydra, showcasing her formidable alien nature. Meanwhile, the Neuralyzed Agent K, played by Tommy Lee Jones, has adopted civilian life under the name Kevin Brown, now serving as a postmaster in a small Massachusetts town. To thwart Serleena’s plan, J must convince Kevin to return to MIB, as he is the sole agent alive who possesses knowledge of the coveted "Light of Zartha."
In a tense moment, as J endeavors to Deneuralyze Kevin, Serleena breaches MIB, triggering a lockdown, leading to a dramatic escape by J and Kevin as they are flushed out of the building. Seeking answers, J brings Kevin to Jack Jeebs, who has crafted an unofficial Deneuralyzer. Although K regains fragments of his memory, he ultimately faces a blank when it comes to the "Light of Zartha," having erased those memories himself. However, clever clues he left behind eventually lead them to a video store, where a tape reveals a past event: 25 years earlier, the Zarthan Queen Laurana attempted to hide the Light on Earth, but the MIB’s strict policy of neutrality led to her rejecting their assistance.
As the story unfolds, it is revealed that Serleena's manipulations continue to escalate; she frees the MIB’s high-security inmates to use as her henchmen. Misled by the belief that the Light is contained within a bracelet worn by Laura Vasquez, a waitress at the pizzeria, Serleena kidnaps Laura, aiming to send her back to her home world. In a climactic battle at MIB headquarters, J and K vanquish Serleena’s henchmen and rescue Laura, but K warns them of dire consequences: if the Light isn’t relocated to Zartha, its explosion could obliterate Earth.
As they hasten to the departure point, Serleena pursues them but meets her end by being devoured by Jeff, a colossal alien worm residing in the New York subway. Eventually, K reveals that Laura is not just any ordinary person—she is Laurana’s daughter and the true Light of Zartha, raising questions about K’s potential paternity. To safeguard both Earth and Zartha, Laura must leave, evoking dismay from J, who had developed feelings for her.
In a final confrontation, Serleena attempts one last time to reclaim Laura but is ultimately destroyed by K and J. To erase the aftermath of Serleena’s chaos, K activates a gigantic Neuralyzer hidden within the Statue of Liberty’s torch. With Laura gone, K and Agent Zed, the head of MIB, attempt to console J, who asserts he requires no solace, having accepted her departure with a clear heart. In a generous gesture, K later surprises J by placing the aliens found in a Grand Central Terminal locker into J's locker as a token. When J expresses how he believes they should show the aliens that their existence extends beyond a mere locker, K unveils to him and Frank the profound truth: that they themselves are an alien species, held within a locker in an alien station, expanding J’s understanding of the universe.
