John awakens to find himself stranded on an island off Seattle. His uncanny abilities are soon apparent to him when he is rescued by Asian fishermen and begins to speak the sailors' language fluently. When he sees a news report about a kidnapped girl, the color-blind Doe realizes that he is seeing the child in color. Sure that she holds the key to the mystery of who he is, Doe is eager to find her and offers his assistance to the skeptical police.

While continuing his quest to figure out who he is and from where he came, John Doe must use all his unique abilities to solve a gruesome murder case, initiated when a seemingly innocent individual dives into a swimming pool which he discovers is filled with human blood. Meanwhile, Lt. Jamie Avery, impressed with Doe's ability to help the police with the case, attempts to surreptitiously learn his real identity. Karen is fired from her waitress job at The Sea and convinces Doe that he needs her as his assistant. Also, a mysterious woman may have information on Doe's identity.

When a young boy Wesley and his mother approach John Doe claiming that sperm bank records indicate he is the boy's father, John is pulled into a mystery as he tries to track down the list of donors and finds two of them dead, their brains removed.