Through newsreel footage, photographs and re-enactments, the life and exploits of Leonard Zelig, the “human chameleon” of the 1920s, is told in documentary fashion. Zelig is seen as an imposter playing for the New York Yankees, a gangster associate of Al Capone, a black jazz musician. In 1926, police investigate the disappearance of a clerk named Leonard Zelig. Only two clues were left behind in his apartment: a photo of Zelig with playwright Eugene O'Neill and another photo of Zelig looking like opera singer Enrico Caruso dressed as “Pagliacci.” Zelig, now seemingly an Asian man, is found in a Chinatown joss house and taken to a psychiatric hospital for questioning. By the time he arrives at the hospital, however, Zelig has turned back into a Caucasian. His hospital report reads in part: "After admittance to the hospital, he seemed to possess a veritable stockpile of different disguises which he donned mysteriously and at a moment's notice, always in an attempt to mock the person he was with. Extremely anti-social, bad manners, low self opinion." When psychiatrist Eudora Fletcher first meets Zelig, she believes him to be a doctor. She becomes fascinated with his case and begins to study his condition. The press is captivated by Zelig, known as “the Changing Man," and he becomes a national celebrity. Under hypnosis, Zelig reveals that he feels safe when he is like other people, and that he wants to be liked. He recalls that his condition first manifested when he was surrounded by a group of smart people who asked if he had read Moby Dick. Zelig was ashamed to admit that he had not read the novel, so he pretended otherwise. Dr. Fletcher receives no support from the psychiatric community, and Zelig's half-sister takes him out of the hospital in hopes of exploiting his strange condition. People flock to see him. Zelig becomes the subject of a 1935 biographical film and several novelty songs, and hundreds of merchandise items are churned out to cash in on his popularity. However, Zelig's public popularity belies the loneliness and isolation he feels when not in the spotlight. Dr. Fletcher seeks to get legal custody of Zelig, but the courts turn her down. Later, when his half-sister is killed by her lover in a murder-suicide, Zelig goes missing again. Although the public is at first fascinated with the mystery of what happened to him, they soon take up other fads and interests. Only Dr. Fletcher keeps looking for the human chameleon. Zelig turns up posing as a Catholic priest in the entourage of Pope Pius XI and is deported back to the U.S., where he is readmitted to Manhattan Hospital. There, Dr. Fletcher steps in to treat Zelig. She takes him to her country home for therapy and engages her cousin, Paul Deghuee, to secretly film their sessions, certain that the record of her work will gain her recognition and attention. Sometime later, in remembering Fletcher’s work with Zelig, famed psychiatrist Dr. Bruno Bettelheim says that in his opinion, despite all the seeming changes in appearance and personality, Zelig was really quite normal and the ultimate conformist. When Dr. Fletcher has no breakthrough with Zelig and cannot convince him that he is not a psychiatrist himself, she tries reverse psychology and asks "Dr. Zelig" for help with her own problems, taking on Zelig's condition as her own. She tells him that she discussed the novel Moby Dick with friends, but in fact had never read the book. He finally breaks down, admits he's not a doctor, and even denies that he is Leonard Zelig. "I'm a nobody," he protests. Using hypnosis, Dr. Fletcher delves into Zelig's personality, and makes post-hypnotic suggestions to modify his behavior. When Zelig is not in a trance, she provides unconditional acceptance and love. In one filmed hypnosis session, Zelig tells Fletcher he hates her cooking and thinks her jokes are boring, but he is in love regardless and wants to go to bed with her. In retrospect, Fletcher reveals that she never thought she was attractive and had never had a real romance before she took up with Zelig. After Dr. Fletcher has spent three months with him, the hospital staff comes to see how he is progressing. He no longer takes on the personalities of those who surround him, but he has gone to the other extreme – so insistent on expressing his own opinions that he cannot abide it when others question them. After a two-week period of adjustment, Zelig is pronounced cured. He and Fletcher are again celebrities, fêted by politicians, newspaper tycoons and movie stars. When asked to give advice to the youth of America, Zelig says they should learn to be themselves. Fletcher finds fame and celebrity less rewarding than she had hoped. She and Zelig marry, and she draws strength from him. When a series of women come forward claiming to be married to Zelig, he is inundated with lawsuits for actions he took when under his various personalities. Zelig's condition deteriorates. At a Greek restaurant with Fletcher, he starts to become Greek. Soon after, Zelig again disappears. Despite a worldwide manhunt, he cannot be found. Finally, in 1932, Fletcher sees a newsreel that shows him at a Nazi party rally. She sails to Europe, but cannot find Zelig. She hears the Nazis will be having their largest rally ever in Munich, Germany, and as she searches the crowd during a speech by Adolph Hitler, she spots Zelig sitting on the podium behind the Nazi chancellor. He recognizes her in the crowd and they wave to each other. The two interrupt Hitler's speech, and in the resulting confusion, manage to escape from the Nazi SS officers pursuing them. An amateur pilot, Fletcher manages to take off in a stolen plane with Zelig, but she becomes terrified and loses control of the aircraft. Zelig takes on the personality of a pilot and flies the plane, eluding the German air force, and managing to set a world record for flying nonstop to the U.S. while upside down. He is received as a hero when they arrive in New York. After managing to sort out his legal troubles, he remarries Fletcher. Zelig's episodes of personality morphing become fewer and fewer, and on his deathbed he only regrets that he has just begun to read Moby Dick.