20,000 years ago, a grumpy mammoth named Manfred and a enthusiastic ground sloth named Sid are left behind during the migration for the ice age. Abandoned by his family, Sid attempts to migrate alone but runs afoul of his two rhinos best friends named Carl and Frank, who try to attack Sid but fail due to Manfred stepping in, only to leave Sid behind afterward. Sid stays with Manfred, referring to the mammoth as "Manny", for protection, much to Manny's dismay.
A tribe of humans camp near a waterfall, among them their leader, named Runar, with his wife Nadia and their infant son Roshan, before heading north to their settlement in the mountains. Soto, leader of a pack of saber-tooth tigers saber-tooth tiger, watches the humans with his trusted lieutenant, a cat named Diego. Soto, seeking revenge against the humans for wiping out half of his pack, intends to devour Runar's son Roshan in vengeance and plans an attack for the next morning. The attack takes place, with Diego pursuing Nadia, but she escapes with Roshan, jumping over the waterfalls so that Diego returns to Soto with no baby; the pack agrees to meet at Half Peak, where Diego will produce the baby for Soto.
Manny and Sid journey on, Manny bothered by the sloth's constant talking, until the two find Nadia on a riverbank, weakened greatly by her jump over the falls, with hardly enough strength to pass her son to Manny before she disappears. Manny leaves, but Sid intends to return the baby to his "herd", which Manny will not help with. The two meet Diego, who takes the baby, claiming that he intends to return him to the humans. Manny, unconvinced, decides to help Sid return the baby to his family, leaving the saber behind; the humans' camp is abandoned and Manny reluctantly decides to head north to find the humans' settlement at Glacier Pass and return the baby, taking Diego along as a guide. The trio takes the baby up north and meets a fanatical flock of dodos on the way, from which they procure food for the baby. During the trek, however, Diego secretly meets up with two of his pack mates, who pass a message from Soto, demanding the baby; Diego sends them back with a message to Soto, promising the baby and Manny. The following morning, Sid takes the baby to a mud crater, where he meets two female sloths named Jennifer and Rachel, who he tries to court using the baby, which Manny takes back; Sid returns to the mud crater, only to find the sloths gone, Carl and Frank in their place. The rhinos pursue Sid, who runs into Diego and pleads to the saber to deter the rhinos: Diego pretends to have killed Sid to throw the rhinos off the trail and releases his grip once the rhinos leave; Diego then moves on with Manny and Sid. On the way, the group runs into a number of predicaments, from a changing landscape to freezing ice age blizzards. The group meets a saber-tooth squirrel named Scrat, who had seen a pack of sabers go by and tries to tell Manny before Diego surreptitiously flicks Scrat away.
Further on, Diego spots the humans close by and suggests a shortcut to waylay Manny and Sid to an ambush point; this shortcut takes them through an ice cavern which leads to a cave adorned with paintings, all featuring animals. Among the paintings is the image of a mammoth family, hunted by humans, which Manny views, revealing that the mammoths depicted were Manny's family and Manny himself: Manny's wife and child were hunted by humans, leaving Manny alive and embittered at the world for his loss. The baby reaches out to the painting, comforting Manny in that he lets go of his bitterness at having lost his wife and child.
Further on, the group grows closer to Glacier Pass when they reach a lava field, which they must cross. Diego nearly falls into the lava but Manny saves him, falling into the lava pit himself as the ice he is standing on breaks off. Manny is launched out of the lava pit unharmed, launched out with the ice he stood on. Diego, in wonderment at Manny's actions, asks why Manny risked his life to save him, Manny replying that such sacrifices where what herds did. Meanwhile, Soto and his pack plan for the ambush on Manny, aided by Diego.
That night, while settling down by campfire, Diego begins to see the error of his ways in betraying Manny. After the others fall asleep, Scrat appears on the scene with his acorn, planning to thaw it from the ice, baking it instead by mistake into a hot kernel. The group continued on, reaching Half Peak, where Diego, feeling remorse for betraying Manny's trust, confesses his plans to Manny, which angers the mammoth. Manny pins Diego to a rock wall, intending to kill him for his misdeeds, but Diego, having had a change of heart, agrees to help Manny escape the pack.
Leading the pack away from Manny, who they intended to ambush, Sid slides off on two pieces of bark with a decoy baby made of snow; the pack, however, catches up with Manny, who knocks them away with a log, trapping Soto's assistant named Zeke, who Sid stomps into a hollow tree. Soto catches up with them and corners Manny, asking Diego to help bring the mammoth down; Diego defects from Soto and defends Manny at his own expense as Soto brings Diego down, wounding him. Soto then turns to Manny, intending to attack him alone, but the mammoth, in vengeance, knocks Soto into an ice wall, which jars loose a number of hanging icicles, impaling him. Sid and Manny abandon the Sabers. Soto and Zeke's friends, Oscar and Lenny, mourn their killed leader as a result.
Manny, Sid and the baby are safe; Diego, however, is severely injured and appears to succumb to his wounds, leaving Manny and Sid to find the humans by themselves. The two find the humans, who ready themselves to attack when Manny produces Roshan, safe and sound. Grateful for Manny's returning Roshan, Runar calls off the attack and bestows a beaded necklace to Manny in thanks before leaving with the baby. Manny and Sid leave and find Diego, who survived the attack due to his "nine lives". The three become a herd and decide to head south together, ending the movie.