It's the Ice Age and the unlikely trio of friends -- Manny (voice of RAY ROMANO) the gruff mammoth, Sid (voice of JOHN LEGUIZAMO) the silly sloth and Diego (voice of DENIS LEARY) the angry saber-toothed tiger -- have found solitude in a peaceful valley surrounded on all sides by mighty glacial walls. Everyone is happy there until hustler Fast Tony (voice of JAY LENO) and a patient vulture (voice of WILL ARNETT) separately bring up the potential impact of global warming on their lives.
Nobody, especially Manny, believes any of that until the mammoth goes up top to stop Sid from doing something crazy to try to prove his worth. They then realize that the glaciers are indeed melting, and should those walls give way, the resultant flood waters would drown everything in the bowl-shaped valley. Accordingly, they all set out for a reported boat that's at the far end of the valley.
Along the way, the trio runs into Crash (voice of SEANN WILLIAM SCOTT) and Eddie (voice of JOSH PECK), a pesky duo of possums whose "sister" Ellie (voice of QUEEN LATIFAH) is unaware that she's really a full-sized mammoth. Manny's happy he's no longer the last of his kind, but the two clash, all as Sid tries to prove he can be a leader and Diego tries to overcome his fear of water.
As the group makes their trek, they must not only put up with their differences, but also two hungry sea monsters that lurk in the rising waters, as well as the inevitable collapse of the valley walls and the resultant massive flood that could sweep all of them away.