Years after the strange events in Kingston Falls, the cute and friendly Gizmo finds himself in a genetics laboratory inside Clamp Center, a state-of-the-art high-rise in Manhattan owned by eccentric billionaire Daniel Clamp. After a chance encounter, Billy Peltzer and his fiancée Kate, both now working in the towering skyscraper, discover their old friend. Remembering the mayhem caused by Mogwai spawning mischievous gremlins, Billy and Kate must ensure that Gizmo stays away from water, bright lights, and food after midnight. Unfortunately, accidents happen, and a splash of water causes Gizmo to spawn a new batch of gremlins, who quickly evolve into wily, mischievous creatures bent on chaos.

The gremlins make their way through the high-tech building, exploiting the complex technological systems and taking full advantage of the gene splicing lab to transform themselves into bizarre mutations. As the creatures run amok, it's a race against time for Billy, Kate, and their friends to prevent the gremlins from multiplying and taking over New York City. Meanwhile, Daniel Clamp sees the unfolding disaster as an opportunity to brand and market his business, oblivious to the growing threat. The gremlins' love for mischief and mayhem makes them formidable opponents, and their unpredictable natures make it difficult for them to be contained as they set their sights on overtaking the skyscraper.