When the Museum of Natural History is closed for renovations, important pieces are moved into storage at other main museums. Haphazard security guard, Larry Daley (Stiller) infiltrates the Smithsonian to rescue Jedediah (Wilson) and Octavius (Coogan) when they are shipped there by mistake.

When writer John Grogan (Owen Wilson) and his wife (Jennifer Aniston) adopt Marley, a yellow Labrador, they intend to get a taste of parenthood. Little did they know, the dog turns out to be a hyperactive handful who wreaks havoc, gets kicked out of obedience school and gets even worse when their children are born, yet becomes a fundamental part of their family. Based on the memoire by John Grogan, the family learns important life lessons from their naughty, neurotic but lovable pet.