Larry Daley, the night guard of New York City's American Museum of Natural History, discovers that the magical tablet responsible for bringing the museum's exhibits to life is corroding. This poses a threat to the lively nighttime activities of his wax figure friends. Seeking a solution, Larry learns that the tablet's origins trace back to the British Museum in London. Determined to save the magic, Larry, his son Nick, and key museum exhibits, including Teddy Roosevelt, Sacagawea, and miniature cowboy Jedediah, travel to London. There, they enlist the help of a newly animated triceratops skeleton and Sir Lancelot.

Upon arriving at the British Museum, chaos ensues as the group encounters new characters and conflicts. Larry and his friends must navigate through various historical and mythological exhibits brought to life by the tablet's power while piecing together clues about its malfunction. With time running out and the stakes higher than ever, Larry must uncover the secret of the tablet's deterioration while keeping the peace among his animated friends and the unsuspecting museum staff.