Maya Dolittle, Kyla Pratt, is a bright teenager who shares her father’s unusual talent: she can talk to animals. Her father, Dr. John Dolittle, is a renowned veterinarian and globe-trotting explorer whose animal-care books have turned him into a celebrity. With John away on expeditions, Maya focuses on her future and applies to San Francisco College's veterinary studies program, which includes a center named after her father.
During the college interview, Maya's grades and SAT scores fall short, and she has no compelling extracurriculars to showcase. She is placed in a real-world test with animal kids, and the situation spirals as the young animals mistake Maya for their mother, leading to a chaotic scene that she struggles to control. She ends up wait-listed, given four weeks to prove herself.
Meanwhile, President Sterling, Peter Coyote, seeks help with his beloved dog Daisy, Jennifer Coolidge, to protect a critical rainforest in Africa. With John traveling, Maya is pressed into service to stand in for her father and tries to secure a POTUS recommendation that could strengthen her college bid.
Maya meets a cast of allies and potential crushes: Cole Fletcher, Niall Matter; Dorian, Malcolm Stewart, the Chief of Staff; Courtney Sterling, Elise Gatien; and Selma Dixon, Christine Chatelain. Sterling explains that Daisy has become more than a pet; she symbolizes his presidency and has attended his inauguration and major events. But Daisy is acting out, urinating and biting visiting dignitaries, threatening the administration’s image. The plan to save the rainforest hinges on the Kalampura prince’s offer; Prince Tharoor, Kwesi Ameyaw, wants to sign a deal with a U.S. company that would destroy the forest. Sterling had previously convinced Tharoor to protect the forest, but at a signing ceremony in Kalampura, Sterling got food poisoning and vomited on Tharoor.
To salvage the situation, Maya must get Daisy under control. After Daisy disrupts the Oval Office, Sterling shifts operations to his ranch, which doubles as a nature reserve he established about 15 years ago. Daisy enlists the help of her animal friends and mounts a coordinated challenge to Maya during a group therapy session. Selma relishes Maya's missteps, telling her she intends to influence global geopolitics by the time she is 30 and questions how Maya can help other animals if she cannot master Daisy.
With encouragement from Sterling, Maya reframes her approach and forges alliances with Daisy's animal companions. She also finds an ally in Cole to help Courtney when she sneaks away from the presidential retreat to a party that goes wrong; they bond over their shared experiences with demanding fathers.
During a dinner with Tharoor and the Kalampura princess, Maya uncovers that Chief Dorian has been sabotaging the deal to profit from the forest's destruction. Dorian had previously supplied Sterling with oysters that caused food poisoning. In a tense moment, Dorian spikes Daisy's food, triggering a wild outburst that jeopardizes the talks and prompts Tharoor to reconsider. A later discovery—evidence from Dorian's safe—proves his plan to profit from the forest, and he is arrested. In the end, Sterling writes a glowing recommendation for Maya to SFU, and she earns admission to the veterinary program.