Laden with laughs, this insightful animation saga sparks off just as two ocellaris clownfish, Marlin and his wife Coral, admire their new home in the Great Barrier Reef and their clutch of eggs, when a barracuda attacks, knocking Marlin unconscious. He wakes up to find that Coral and all but one of the eggs have disappeared. Marlin names this last egg Nemo, a name that Coral liked.
Nemo develops a smaller right fin as a result of damage to his egg during the attack, which limits his swimming ability. Worried about Nemo's safety, Marlin embarrasses Nemo during a school field trip. Nemo sneaks away from the reef and is captured by scuba divers. As the boat departs, a diver accidentally knocks his diving mask overboard.
While attempting to save Nemo, Marlin meets Dory, a good-hearted and optimistic regal blue tang with short-term memory loss. Marlin and Dory meet three sharks – Bruce, Anchor and Chum – who are trying to make friends with fish in an old minefield. Marlin discovers the diver's mask and notices an address written on it. When he argues with Dory and accidentally gives her a nosebleed, the blood scent causes Bruce to enter an uncontrollable feeding frenzy. The pair escape from Bruce but the mask falls into a trench in the deep sea.
During a hazardous struggle with an anglerfish in the trench, Dory sees the diving mask and reads the address located in Sydney, Australia. The pair swim on, receiving directions to Sydney from a school of moonfish. Marlin and Dory encounter a bloom of jellyfish that nearly kills them. Marlin loses consciousness and wakes up on a sea turtle named Crush, who takes Marlin and Dory on the East Australian Current. Marlin tells the details of his long journey with a group of sea turtles, and his story is spread across the ocean. He also sees how Crush gets on well with his son Squirt.
Meanwhile, Nemo is placed in a fish tank in the office of a dentist named Phillip Sherman on Sydney Harbour. He meets aquarium fish called the Tank Gang, led by a moorish idol named Gill, who has a broken fin. The Tank Gang includes Bloat, a puffer fish; Bubbles, a yellow tang; Peach, an ochre starfish; Gurgle, a royal gramma; Jacques, a pacific cleaner shrimp; and Deb, a blacktailed humbug.
The fish learn that Nemo is to be given to Sherman's niece, Darla, who killed a fish by constantly shaking its bag. Gill then reveals his plan to escape, jamming the tank's filter, forcing the dentist to remove the fish to clean it. The fish would be placed in plastic bags, and then they would roll out the window and into the harbor. After an attempt at the escape goes wrong, a brown pelican, Nigel, brings news of Marlin's adventure. Inspired by his father's determination, Nemo successfully jams the filter, but the dentist installs a new high-tech filter before they can escape.
After leaving the East Australian Current, Marlin and Dory are engulfed by a blue whale. Inside the whale's mouth, Dory communicates with the whale, which carries them to Port Jackson and expels them through his blowhole. They meet Nigel, who recognizes Marlin from the stories he has heard, and he takes them to Sherman's office. Darla has just arrived and the dentist is handing Nemo to her. Nemo plays dead to save himself as Nigel arrives.
Marlin sees Nemo and believes he is dead before Nigel is thrown out. In despair, Marlin leaves Dory and begins to swim home. Gill then helps Nemo escape into a drain that leads to the ocean. Dory loses her memory and becomes confused, and meets Nemo, who reached the ocean. Eventually, Dory's memory returns after she reads the word "Sydney" on a drainpipe.
She directs Nemo to Marlin and they reunite, but then Dory is caught in a fishing net with a school of grouper. Nemo enters the net and orders the group to swim downward to break the net, enabling them to escape. After returning home, Nemo leaves for school, with Crush's son Squirt, and Marlin, no longer overprotective, proudly watches Nemo swim away with Dory at his side.
At the dentist's office, the high-tech filter breaks down and the Tank Gang escapes into the harbor, belatedly realizing they are still confined in plastic bags.