Dr. John Dolittle (Robert Downey Jr.) is a vet who can talk to animals. After his wife Lily (Kasia Smutniak) dies at sea, Dolittle confines himself to his home and attending his animals, no longer wanting contact with humans. One day, a boy named Tommy Stubbins (Harry Collett) accidentally shoots and wounds a squirrel, and decides to go to Dolittle for help.
On the same day, Queen Victoria (Jessie Buckley) sends a message, ordering Dolittle to come in order to try to cure her of a deadly sickness. After being persuaded by the animals, Dolittle finally decides to go. Upon reaching her, he finds that the Queen has eaten a poisonous type of nightshade. To be cured, she must eat a fruit from a land far away. Dolittle, Stubbins, and a crew of animals put to sail, hoping to find the cure while trying to avoid Dolittle’s rival.
Dolittle is captured by Rassouli (Antonio Banderas), his ex-father-in-law, and is locked in a cage with Barry, a tiger only looking for his mothers approval. Just when it looks like Dolittle is in trouble, Chee-Chee the Gorilla breaks in and hits Barry. Dolittle and Stubbins escape only to be captured by Dr. Blair and have their ship destroyed. After seeing a discouraged Dolittle, Rassouli loans him a boat.
Dolittle and company arrive at an island where they meet Ginko-Who-Soars, an angry fire breathing dragon. Ginko begins attacking before she falls due to pain. Dolittle figures what is hurting Ginko and proceeds to remove armour and bagpipes (from previously eaten trespassers) from Ginko’s behind. A relieved Ginko shows Dolittle the tree with the cure. Stubbins gives the queen the plant which cures her. A walking stick that Dolittle left behind announces that Lord Thomas poisoned the queen. Dolittle reopens the doors to his sanctuary now including Stubbins.
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