Sinbad (voice of BRAD PITT), the sailor and opportunistic thief, is looking to steal the powerful Book of Peace that protects twelve cities and their citizens. Along with his pet dog Spike, right-hand man Kale (voice of DENNIS HAYSBERT) and the rest of his crew, he boards the ship carrying the book. Unbeknownst to him, his former childhood friend and current Prince of Syracuse, Proteus (voice of JOSEPH FIENNES), is commanding that ship and won't let the book go so easily.
Little do either of them know that Eris (voice of MICHELLE PFEIFFER), the Goddess of Chaos, also wants the book in order to make the entire world more chaotic. Her intervention allows Proteus and his ship to sail away, so she makes a deal with Sinbad. She'll allow him to live if he brings the book to her in Tartarus.
He agrees and thus arrives in Syracuse, intent on finally getting his hands on the book. Eris decides to have a little fun with him, however, by taking his shape and stealing the book, thus making everyone think he has it. Sentenced to die by the city council, Sinbad can't believe his luck. Yet, it changes when Proteus volunteers to take his place, knowing that his former friend wouldn't let him die over the book.
Given ten days to return it, Sinbad sets sail but plans to go to Fiji rather than Tartarus since he figures the King won't allow his only son to be executed. That doesn't sit well with Proteus' independent and resourceful fiancée, Marina (voice of CATHERINE ZETA-JONES), who's set to marry the prince in an arranged marriage. Although they're like oil and water, Sinbad agrees to find Eris, retrieve the book and save Proteus' life when the Ambassador offers him a large financial reward.
From that point on, they sail the high seas headed for Tartarus and must deal with a variety of potentially deadly obstacles that Eris places in their way, all as Sinbad has a change of heart and eventually begins to fall for Marina.