After losing his wife (Kasia Smutniak) seven years earlier, the eccentric Dr. John Dolittle (Downey), famed doctor and veterinarian of Queen Victoria's England, hermits himself away behind the high walls of Dolittle Manor with only his menagerie of exotic animals for company.

But when the young queen (Jessie Buckley) falls gravely ill, a reluctant Dolittle is forced to set sail on an epic adventure to a mythical island in search of a cure, regaining his wit and courage as he crosses old adversaries and discovers wondrous creatures.

The doctor is joined on his quest by a young, self-appointed apprentice (Harry Collett) and a raucous coterie of animal friends, including an anxious gorilla (Rami Malek), an enthusiastic but bird-brained duck (Octavia Spencer), a bickering duo of a cynical ostrich (Kumail Nanjiani) and an upbeat polar bear (John Cena) and a headstrong parrot (Emma Thompson), who serves as Dolittle's most trusted advisor and confidante.