Right after Shrek and Princess Fiona's honeymoon, the newly wed couple goes to Princess Fiona's parents for dinner. When a Fairy Godmother discovers Fiona and Shrek are married she reminds the king about a deal they agreed on years ago, that Fiona should have married her son, who happens to be Prince Charming. The King then hires a cat named Puss-in-Boots, a sword fighting cat and ogre slayer, to kill Shrek.

After losing his wife seven years earlier, the eccentric Dr. John Dolittle, famed doctor and veterinarian of Queen Victoria's England, hides behind the walls of Dolittle Manor with only his menagerie of exotic animals for company. But when the young queen falls gravely ill, a reluctant Dolittle is forced to set sail on an epic adventure to a mythical island in search of a cure. The doctor is joined on his quest by a young, self-appointed apprentice...