Dory, a regal blue tang, gets separated from her parents as a child. As she grows up, Dory attempts to search for them, but gradually forgets them due to her short-term memory loss disability. In the flashback of the previous film, Finding Nemo, she joins Marlin – a clownfish looking for his missing son Nemo – after accidentally swimming into him.
One year later, Dory is living with Marlin and Nemo on their reef. One day, Dory has a flashback and remembers that she has parents. She decides to look for them, but her memory problem is an obstacle. She eventually remembers that they lived at the Jewel of Morro Bay across the ocean in California.
Marlin and Nemo accompany Dory. With the help of Crush, a sea turtle friend, they ride a water current to California. Upon arrival, Dory accidentally awakens a squid, who immediately pursues them and almost devours Nemo. Marlin berates Dory for endangering them. Her feelings hurt, Dory travels to the surface to seek help and is captured by staff members from the nearby Marine Life Institute after getting entangled in six pack rings.
Dory is placed in the quarantine section and tagged. There she meets a grouchy but well-meaning octopus named Hank. Dory’s tag shows that she will be sent to an aquarium in Cleveland. Due to a traumatic ocean life, Hank wants to live in the aquarium instead of being released back into the ocean, so he agrees to help Dory find her parents in exchange for her tag. In one exhibit, Dory encounters her childhood friend Destiny, a nearsighted whale shark who used to communicate with Dory through pipes, and Bailey, a beluga whale who mistakenly believes he has lost his ability to echolocate. Dory subsequently has flashbacks of life with her parents and struggles to recall details. She finally remembers how she was separated from her parents: she overheard her mother crying one night, left to retrieve a shell to cheer her up, and was pulled away by an undertow current.
Marlin and Nemo attempt to rescue Dory. With the help of two sea lions named Fluke and Rudder and a disfigured common loon named Becky, they manage to get into the institute and find her in the pipe system. Other blue tangs tell them that Dory’s parents escaped from the institute a long time ago to search for her and never came back, leaving Dory believing that they have died. Hank retrieves Dory from the tank, accidentally leaving Marlin and Nemo behind. He is then apprehended by one of the employees and unintentionally drops Dory into the drain, flushing her out to the ocean. While wandering aimlessly, she comes across a trail of shells; remembering that when she was young, her parents had set out a similar trail to help her find her way back home, she follows it. At the end of the trail, Dory finds an empty home with multiple shell trails leading to it. As she turns to leave, she sees her parents Jenny and Charlie in the distance. They tell her they spent years laying down the trails for her to follow in the hopes that she would eventually find them.
Marlin, Nemo, and Hank end up in the truck taking various aquatic creatures to Cleveland. Destiny and Bailey escape from their exhibit to help Dory rescue them. Once on board the truck, Dory persuades Hank to return to the sea with her, and together, they hijack the truck and drive it over busy highways, creating havoc, before crashing it into the ocean, freeing all the fish. Dory, along with her parents and new friends, return to the reef with Marlin and Nemo.
In a post-credits scene, the Tank Gang from Finding Nemo, still trapped inside their (now algae-covered) plastic bags, reach California one year after floating across the Pacific Ocean, where they are eventually picked up by staff members from the Marine Life Institute.