As all the animals migrate south to avoid the colder weather, Manny the lonely Mammoth heads against the current. Sid the giant sloth, who slept through the start of the great migration, gets himself in trouble with two shovel-nosed rhinos. In an attempt to escape the angry rhinos, Sid hides behind Manny, who becomes his unlikely hero. Meanwhile, a family of Neanderthals celebrate a new child as a pack of Sabre-toothed tigers watch on, plotting their revenge.
Manny and Sid find an injured mother, who gives them her child. Sid is determined they do the right thing, but Manny argues there is no "they", following Sid only out of curiosity. Diego the sabre-toothed tiger attempts to pinch the child, and Manny decides to return baby Roshan himself. Reaching the human's camp, they see it abandoned, and Diego becomes a part of the unlikely team. Together they must learn to work together to care for the child.
Manny, Sid, Diego and baby Roshan set up camp for the night. Two members of Diego's pack visit him while the others sleep, sending a threat from their leader, Soto. Sid uses the baby to impress two female sloths but gets himself into the usual trouble. The four set out towards Glacier Pass, taking on different familial roles and finding humour in friendship.
Diego suggests a shortcut. Locked in a cave, they pass fossils from the Palaeocene, Miocene and some of the earliest organisms, even some objects from science fiction. When Roshan slips down a tunnel, they are forced to follow. The scene resembles contemporary human activities, such as luging and theme parks. After they recover the child, Manny, Sid and Diego discover a cave full of paintings and learn a little more about how Manny lost his family to human hunters.
Manny, Diego and Sid make it to Half Peak, but the ground erupts with lava. Manny sees Diego struggling on a ledge and saves him, almost sacrificing himself in the process. Diego is thankful but bewildered by Manny's actions, and Manny responds, "That's what you do in a herd." Meanwhile, the other sabre-toothed tigers lie in wait to intercept the troupe. Sid, Diego and Manny set up camp, Sid discovers fire, and the baby takes his first steps. Diego agonises over his dishonesty.
Diego confesses he was leading his new friends into a trap but tries to redeem himself. Sid distracts the sabre-toothed tigers, while Diego and Manny sneak past, but Soto finds them. Diego is gravely injured when he defies his pack to protect Manny, echoing Manny's sentiment of the importance of caring for your herd. Sid and Manny go alone to return the baby, proving than empathy is deeper than cultural differences.
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