Three American brothers who have not spoken to each other in a year set off on a train voyage across India with a plan to find themselves and bond with each other -- to become brothers again like they used to be. Their "spiritual quest", however, veers rapidly off-course (due to events involving over-the-counter pain killers, Indian cough syrup, and pepper spray).

Renowned oceanographer Steve Zissou has sworn vengeance upon the rare shark that devoured a member of his crew. In addition to his regular team, he is joined on his boat by Ned, a man who believes Zissou to be his father, and Jane, a journalist pregnant by a married man. They travel the sea, all too often running into pirates and, perhaps more traumatically, various figures from Zissou's past, including his estranged wife, Eleanor.