Ursula Stanhope (Leslie Mann) is a beautiful, blonde San Francisco heiress, reluctantly engaged to marry Lyle Van De Groot (Thomas Haden Church), who seems more attached to his fiancee's wealth than to her. On an expedition to Central Africa, joined by Lyle, two poachers hired by Lyle named Max and Thor, and a quartet of African men led by Mr. Kwame, Ursula learns of the legend of the "White Ape" from Mr. Kwame. The legend describes the ape as a super strong man who rules the jungles of Africa. The group discover the Ape Mountain where the White Ape lives. Lyle causes trouble for Ursula and her porters, one of them falling off a rope bridge when Lyle shakes it about and he then abandons Ursula when the two are attacked by a lion. Ursula is saved by the White Ape, revealed to be a Tarzan-like man named George (Brendan Fraser). George takes her to his treehouse home where the rest of his family lives - an intelligent talking ape named Ape (John Cleese); Shep, George's pet "dog", really an African elephant; Tookie Bird, a toucan; and Little Monkey, a small monkey. George has a habit of crashing into trees while vine-swinging and is rather childish. He falls in love with Ursula, attempting to impress her like a gorilla but when this fails, he instead dances with her around a campfire.

Lyle, Max, Thor, Kwame and the porters (who spend most of the film speaking in Swahili, but it is revealed they speak English) search for Ursula. Lyle, Max and Thor locate Ursula but when George runs in to defend Ursula, Lyle shoots him with a pistol, believing it was a cigar lighter. George survives (as according to the Narrator, no one dies in the film and he's the hero) and is taken to San Francisco by Ursula where he finds this "jungle" completely different from his own. He is introduced to Ursula's proud parents, Beatrice (Holland Taylor) and Arthur (John Bennett Perry), Beatrice being very distraught when she hears Lyle is in prison. She tells George in a way he will understand that he and Ursula can never become a couple. Tookie Bird appears to George and tells him that Ape was kidnapped by Max and Thor who plan to use him to become rich and famous. George returns to Africa, with Ursula not far behind. George locates Max, Thor and Ape at his treehouse where he, Ursula and George's animal family defeat the two. Lyle appears, having escaped prison and becoming a ceremonial minister. He kidnaps Ursula to forcefully make her marry him. George manages to escape five of Lyle's men and chases the two who end up falling down some river rapids. George performs "the biggest swing in jungle history" to save Ursula while Lyle ends up getting married to a lovestruck kissing female gorilla.

After admitting they love each other, George and Ursula are married in a lavish jungle celebration and eventually have a son named George Jr. George holds Jr. at the top of the pride rock, and all the animals are gathered there to see him, similar to The Lion King, where Rafiki held Simba. At the end, Ape travels to Las Vegas, Nevada where he becomes a performer, and the final scenes show him using Max and Thor as stage props in his program.