In 1845, in the small port town of Puddleby-on-the-Marsh, England, Matthew Mugg brings his young friend Tommy Stubbins with him when he takes an injured duck to his friend, the eccentric Doctor John Dolittle, who he claims is the best veterinarian in the world because he can talk to animals. A former medical doctor, Dolittle lives with a large menagerie of various creatures, including a talking blue-and-yellow macaw named Polynesia, a chimpanzee named Chee-Chee, a dog named Jip, and a piglet named Gub-Gub. He explains that the many animals he kept in his home created havoc with his human patients who began to go elsewhere for their medical needs, so his sister Sarah who served as his housekeeper demanded that he dispose of the animals or she would leave. He chose the animals. Polynesia then revealed that she could speak over 2,000 animal languages and offered to teach Dolittle so he could become an animal doctor. Dolittle says he can now speak nearly 500 animal languages and he is currently in the process of learning how to speak with sea creatures for an upcoming expedition to search for the legendary Great Pink Sea Snail.

The next morning, Dolittle is treating a horse for near-sightedness when the horse's owner, the local magistrate General Bellowes, bursts in and accuses him of stealing the animal. Bellowes ends up getting chased away by skunks and his niece Emma Fairfax chides Dolittle for his rudeness and lack of compassion for humans. Dolittle expresses his contempt for her uncle, who hunts foxes, and for her, who, he says, does absolutely nothing, and she storms off.

To help Dolittle earn money for his expedition, a friend sends him a rare pushmi-pullyu, which is a creature that looks like a llama with a head on each end of its body and that likes to dance. Dolittle takes the pushmi-pullyu to a nearby circus run by Albert Blossom, and it becomes the star attraction. The doctor talks with a sad seal named Sophie and learns she longs to return to her husband at the North Pole, so he smuggles her out of the circus, disguises her in women's clothing to convey her to the coast, and throws her in the ocean. Some fishermen witness this and have Dolittle arrested for murder.

When he appears in court before Bellowes, Dolittle is able to prove he can converse with animals by talking with Bellowes's dog and revealing details only Bellowes and the dog could know. Certain he will be set free, he tells Matthew to get ready to begin their expedition the next day. While he is acquitted on the murder charge, the vindictive Bellows orders him committed to an insane asylum.

Polynesia engineers Dolittle's escape during his transfer to the asylum by obtaining the cooperation of the police horses and dogs. Dolittle, Matthew, Tommy, Polynesia, Chee-Chee, and Jip set sail in search of the Great Pink Sea Snail. Dolittle is surprised to discover Emma, who has become fascinated by him and is seeking adventure, is also on board his ship the Flounder. As he will be arrested if he turns back, he agrees to let her be his cook and cabin boy. It is decided by randomly pointing at a map that the crew will search for the Snail on Sea Star Island which is a floating island that is probably currently somewhere off the western coast of Africa. Assisted by various sea creatures, they near the Sea Star Island where they encounter a violent storm and the Flounder is des…

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• Rex Harrison as Doctor John Dolittle, an eccentric veterinarian who can communicate with animals
• Samantha Eggar as Emma Fairfax (singing voice dubbed by Diana Lee), General Bellowes' niece, who accompanies Doctor Dolittle on his voyage. The character was created for the film.
• Anthony Newley as Matthew Mugg, Doctor Dolittle's friend and assistant
• Richard Attenborough as Albert Blossom, the owner of a circus
• Peter Bull as General Bellowes, Emma's uncle who is the magistrate of Puddleby-on-the-Marsh. The character was created for the film.
• Muriel Landers as Mrs. Edie Blossom, Albert's wife
• William Dix as Tommy Stubbins, Matthew's young friend
• Geoffrey Holder as William "Willie" Shakespeare X (read: the tenth), the chieftain of Sea Star Island. The character is loosely based on Prince Bumpo from Lofting's books.
• Portia Nelson as Sarah Dolittle, Doctor Dolittle's sister who used to be his housekeeper
• Norma Varden as Lady Petherington, Doctor Dolittle's hypochondriac patient
• Jack Raine as the Vicar, Doctor Dolittle's patient with hay fever (uncredited)
• Arthur Gould-Porter as Sir Rupert, Doctor Dolittle's patient with an injured foot (uncredited)
• Ginny Tyler as the voice of Polynesia, Doctor Dolittle's talking pet blue-and-yellow macaw (uncredited)

The film's first test screening took place in September 1967 at the Mann Theatre in Minneapolis, and it was a failure. The audience consisted mainly of adults, who were not the primary target audience, and the general response during the screening was muted. Comment cards rated the film poorly, with frequent complaints about the length, so, in an attempt to improve the pacing, several verses were dropped from the songs, including "Beautiful Things", and the song "Where Are the Words?" was removed before the film was screened again in San Francisco. The shorter edit screened to a younger audience in a different city was no more successful, so additional edits were made, including the removal of the song "Something in Your Smile", before the film was screened in San Jose, California. This version of the film, which ran 151 minutes, was received well enough to be approved as the final cut.

In October, as the film's release date approached, Helen Winston sued 20th Century Fox for $4.5 million alleging that the plot point about animals threatening to go on strike on Dolittle's behalf was plagiarized from her screenplay. As Bricusse had read Winston's script and, assuming this idea was from one of Lofting's books, included it in his treatment, the producers had no legal defense and were forced to settle out of court. The animal strike is mentioned at the end of the movie, but was not actually filmed.