The film opens with John Dolittle as a child talking to his dog (voiced by Ellen DeGeneres). He asks his dog questions, one being "Why do dogs sniff each other's butts"? Her response is that it's their way of shaking hands. His concerned father (Ossie Davis) hears the question and says that the dog doesn't have any idea what he said. He was wrong. He finds this out when John meets his new principal and sniffs his butt. The dog obviously knows something is going to happen. When his father hires a minister to remove the devil from him (and freaking him out), the dog saves him by biting the minister. The dog is then given-up for adoption. John is very upset and stops talking to animals as his father teaches him to hate them.
Thirty years later, we see John Dolittle (Eddie Murphy) shooing a puppy out of his apartment. He is a doctor, married with two children, and an animal hater. His 13-year-old daughter Charisse (Raven-Symoné) wants to be named Paprika. His youngest daughter Maya (Kyla Pratt) is a nerdy girl who does experiments, such as raising what she believes to be a swan egg so it will bond with her. She also has a Guinea Pig named Rodney (voiced by Chris Rock). John's wife Lisa (Kristen Wilson) wants to spend time with him. Meanwhile at work, a large medical company owner named Calloway (Peter Boyle) wants to buy his practice. This is welcomed by the employees as they think it will bring financial gain.
John takes his family out to the country for a vacation. After taking the family to the country, he has to stay late at work to give Mrs. Parkus (Cherie Franklin), a woman who is addicted to shellfish in spite of the fact that she is highly allergic to it, medication.
Driving home, he nearly hits a dog and bumps his head on the windshield. Alive and well, the mutt walks away and shouts "Watch where you're going next time, you bone-head!". This is the first time that John has understood an animal since his childhood. The next day, John is driving Rodney to the country and Rodney starts talking to him.
Up in the country, an owl (voiced by Jenna Elfman) asks him to remove a twig in her wing. He obliges and she tells all the animals about his kind act. Soon many animals start asking favors of John. Scared, he goes to see Dr. Sam Litvak (Steven Gilborn) for a CAT scan, but nothing is wrong with him. The next day he finds the dog he nearly hit being taken to a kennel. John rescues the dog, and takes him to the vet. Slowly becoming friends, John and the later decide his name should be 'Lucky'.
John makes a deal with Maya. If she stays at camp, John will give her Lucky. That night a large bunch of animals come to see the Doctor for treatment, including a drunken circus monkey, two dysfunctional pigeons, a goat with a rash, an OCD dog, and a pair of cloned sheep with rectal trauma. Along the way, John relearns to appreciate his gift and confides in Lucky that he feels more energized about his work than he has in years. After he fits a nearsighted police horse for special glasses, the drunken monkey tells the doctor about a sick circus tiger (voiced by Albert Brooks). They find the tiger, named Jake, on top of Coit Tower attempting to commit suicide. John and Lucky attempt to stop him, saying that everyone loves tigers (using Tony the Tiger and "Eye of the Tiger" as examples) and that John can cure him. His work with animals distracts him from a meeting with Calloway and from spending time with his wife. Soon, Lisa discovers all the animals.
She and Mark catch him giving CPR to a group of rats (Reni Santoni and John Leguizamo), which was a false alarm (a.k.a Gas) while conversing with the other one. Thinking he is crazy, his friends and family send him to an asylum where he meets Blaine (an uncredited Paul Giamatti), an enemy of John from medical school. Meanwhile, the Tiger is getting sicker, so Lucky tries to break John out of the asylum. John is mad at all the animals for sending him to the asylum, but Lucky says that he is hiding from his true self. Declaring that he will not talk to animals anymore, John is released. Maya, at home because she did not fit in, tells her Grandpa that she believes her dad has the gift of gab. Overhearing this, he realizes his mistake and apologizes to Lucky. Later, during the party where Calloway will buy the company, John and Lucky go to the circus, pick up Jake, and take him to the clinic so they can cure him. Meanwhile, the police are after John, but Lucky gathers all the animals of San Francisco to help guard the building in which John is operating on the tiger.
But because they need to go through the party, and because Rodney is there, Jake comes out from under the hospital bed and scares everyone. Soon everyone is watching the operation. Lisa is now upset that her husband thinks he can talk to animals. John's father finally reveals that he, in fact, can. With that said, she comes in the operating room to comfort Jake. John finds out that Jake is suffering from a blood clot stuck in his head, and with that, saves his life. Calloway is watching this and he is very impressed. He wants to buy the company, but John declines his offer.
In the end, John is now a both human doctor and a veterinarian. Maya's egg hatches, revealing it to be an alligator. John and Lucky are seen walking to the circus to visit Jake and talking about their future as friends while the song "Talk with the Animals" plays in the background.
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