Larry Daley is a divorced father who can't seem to keep a job for more than a week. As a last resort, Larry applies for a job as a night shift security guard at the American Museum of Natural History. However, a seemingly easy job turns out to be an adventure when he finds that an ancient curse causes the "inhabitants" of the museum to come to life at night.

Follow Central Park Zoo animals, including, Alex the Lion, Marty the Zebra, Melman the Giraffe and Gloria the Hippo, along with the psychotic penguins, the monkeys, and the lemur leaders as they unexpectedly are now stranded in the middle of Africa. While Alex, Marty, Melman and Gloria are rather happy with their new environment, they quickly realize that it's not all that it seems. Meanwhile, the penguins attempt to repair the plane that they accidentally...