Reggie the Turkey (Owen Wilson) has always been afraid of Thanksgiving because turkeys have always been on the menu. However, his attempts to warn his farm-based flock constantly fall on deaf ears and has made him an outcast. When the other turkeys finally realize what's going on, they throw Reggie to the wolves in an attempt to save themselves. In a surprise twist of fate, he winds up being named the "pardoned turkey" by the President of the United States (Jimmy Hayward) and is subsequently taken to Camp David. Although initially hesitant, Reggie soon eases into a routine of doing nothing but enjoying pizza delivered to him by the Pizza Dude (Scott Mosier) and watching telenovelas.
About three days before Thanksgiving, Reggie gets bag-kidnapped by Jake (Woody Harrelson), the president and the only member of Turkeys Liberation Front. Jake tells him that a "Great Turkey" told him to find Reggie and take him back to the first Thanksgiving with him to take turkeys off the menu once and for all. Despite interference by federal officials and several attempts by Reggie to trick him back to the surface, Jake manages to commandeer an egg-shaped time machine with an A.I. software named S.T.E.V.E. (George Takei) and takes Reggie with him back to the same day in 1621. Once there, they are immediately attacked and separated by colonial hunters led by Myles Standish (Colm Meaney). Reggie and Jake are quickly rescued by native turkeys led by Chief Broadbeak (Keith David) and his two children Ranger (Jimmy Hayward) and Jenny (Amy Poehler), the latter of whom Reggie is immediately smitten with. Broadbeak explains that the turkeys in the area have been forced underground since the settlers came and that they can't risk fighting back without the settlers taking them.
The next day, Broadbeak has Jake go with Ranger to spy on the settlers with Reggie and Jenny spring all the hunting traps they've set up. Despite initial hostility, Ranger and Jake find out that the settlers have already begun preparations for Thanksgiving as well as where they keep their weapons. Meanwhile, Jenny, who believes Reggie is lying about being from the future, is impressed with his unorthodox way of springing the traps. However, they are soon intercepted by Standish and Reggie is forced to get her in orbit over the planet aboard S.T.E.V.E., validating everything he said in the process. Reggie tries to convince Jenny to go back to the future with him once everything blows over, but she tells him she can't bring herself to leave the flock no matter how much she likes him.
Jake drags Reggie away from Jenny and tells him he has a plan to attack the settlers. However, Reggie has gotten sick of all his unproved stories and threatens to leave. Desperate, Jake tells him that this trip was more about him making up for him not being able to save three turkey eggs while escaping a turkey-fattening facility when he was younger, although still maintaining that the Great Turkey convinced him to go through with this. While still reluctant to believe what he said, Reggie still goes along with the plan. They manage to use gunpowder to destroy the weapons shack, but Jake inadvertently leaves a gunpowder trail back to the tree the turkeys are hiding under. Standish and his men flush the turkeys out from underground, capturing enough for the feast and killing Broadbeak in the ensuing panic. Jenny is sworn in as the new chief and orders the remaining turkeys to prepare an attack on the settlers.
Despite Jake's attempts to get him to stay, a heartbroken Reggie heads back to the present. Once back at Camp David, Reggie is confronted by three future versions of himself. Through the awkward conversation, Reggie discovers from one of them that he was the Great Turkey, having used S.T.E.V.E. to throw his voice and appearance. Inspired, Reggie goes back in time to stop the attack, erasing Standish from history in the process. Through S.T.E.V.E. and the Pizza Dude (who was also brought back to the First Thanksgiving), Reggie convinces the settlers and the arriving Indians that pizza is a more acceptable food than turkeys, taking them off the Thanksgiving menu entirely.
In the end, Reggie decides to stay with Jenny while Jake takes S.T.E.V.E. in order to look for new adventures. However, Jake returns moments after leaving and implies to Reggie and Jenny that their antics have caused the future to be thrown out of whack.