John Dolittle (EDDIE MURPHY) is a San Francisco-based doctor who not only treats humans, but also animals with which he can communicate, including Lucky, the dog (voice of NORM MACDONALD), the Drunk Monkey (voice of PHIL PROCTOR) and Pepito (voice of JACOB VARGAS), a pet chameleon who can't change color. This obviously leads to a busy appointment schedule, something that's put a strain on his relationship with his family, including Lisa (KRISTEN WILSON), his wife, and their daughters Maya (KYLA PRATT) and Charisse (RAVEN-SYMONÉ).
When he discovers that Charisse would rather spend her sixteen birthday with her boyfriend Eric (LIL' ZANE) than them, Dolittle decides it's time for a family vacation. That plan is derailed, however, when the doc receives several visits from Joey the Raccoon (voice of MICHAEL RAPAPORT) and the Possum (voice of ISAAC HAYES) who want him to meet the God Beaver (voice of RICHARD C. SARAFIAN), the head of the local animal union.
The Beaver is concerned because lumber tycoon Joseph Potter (JEFFREY JONES) and his ruthless lawyer Jack Riley (KEVIN POLLAK) have taken steps to level their forest and the animals believe that Dolittle is the only human who can save their homes. Realizing the only way to stop the developers is to find an endangered species in the path of the deforestation, Dolittle discovers that a lone Pacific Western bear, Ava (voice of LISA KUDROW), lives in the forest.
Yet, she needs a mate and offspring for his plan to work, so Dolittle enlists the aid of Archie (voice of STEVE ZAHN), a circus performer bear to become Ava's suitor. The only problem is, she already has a bear boyfriend, Sonny (voice of MIKE EPPS), and Archie doesn't exactly know his way around the forest.
Thus, with just 30 days and counting on a court ordered suspension of leveling the woods, Dolittle takes his family out into the forest where he hopes to train the reluctant and skeptical Archie about how to be a real bear, all while Potter and Riley do what they can to stop that from happening.