Set in the 1920s and 1930s, the film focuses on Leonard Zelig, a nondescript man who has the ability to transform his appearance to that of the people who surround him. He is observed at a party by F. Scott Fitzgerald, who notices that while mingling with the guests, Zelig sings the praises of the affluent classes in a refined, snobbish accent, but while in the kitchen with the servants, he seethes with rage at the fat cats in a thick proletarian voice. He soon gains international fame as a "human chameleon".
Dr. Eudora Fletcher (Mia Farrow) is a psychiatrist who wants to help Zelig with this strange disorder when he is admitted to her hospital. Through the use of hypnotism, she discovers Zelig yearns for approval so strongly he physically changes to fit in with those around him. Dr. Fletcher's determination allows her to cure Zelig, but not without complications; on the road to recovery, he temporarily develops a personality which is intolerant of other people's opinions.
Dr. Fletcher realizes she is falling in love with Zelig. Due to the media coverage of the case, both patient and doctor become part of the popular culture of their time. However, fame is the main cause of their division; the same society that made Zelig a hero destroys him.
Zelig's illness returns, and he tries to fit in once more. Numerous women claim he married them, and he disappears. Dr. Fletcher finds him in Germany working with the Nazis prior to the outbreak of World War II. Together they escape and return to America, where they are proclaimed heroes (after Zelig, using his ability to imitate one more time, mimics Fletcher's piloting skills and flies back home across the Atlantic upside down).
Woody Allen used actual newsreel footage and inserted himself and other actors into the footage via bluescreen technology. To provide an authentic look to his scenes, Allen and cinematographer Gordon Willis used a variety of techniques, including locating some of the actual antique film cameras and lenses used during the eras depicted in the film, and even going so far as to simulate damage, such as crinkles and scratches, on the negatives to make the finished product look more like vintage footage. The virtually seamless blending of old and new footage was achieved almost a decade before digital filmmaking technology made such techniques in films like Forrest Gump and various television commercials much easier to accomplish.
The film uses cameo appearances by real figures from academia and other fields for comic effect. Contrasting the film's vintage black and white film footage, these individuals appear in color segments as themselves, commenting in the present day on the Zelig phenomenon as if it really happened. They include essayist Susan Sontag, psychologist Bruno Bettelheim, Nobel Prize-winning novelist Saul Bellow, political writer Irving Howe, historian John Morton Blum, and the Paris nightclub owner Bricktop.
Also appearing in the film's vintage footage are Charles Lindbergh, Al Capone, William Randolph Hearst, Marion Davies, Charlie Chaplin, Josephine Baker, Fanny Brice, Adolf Hitler, Josef Goebbels, Hermann Goering, James Cagney, Jimmy Walker, Lou Gehrig, Babe Ruth, Bobby Jones, and Pope Pius XI.
The soundtrack includes such period songs as "I'm Sitting on Top of the World" and "Five Feet Two, Eyes of Blue" by Ray Henderson, Sam Lewis, and Joe Young; "Sunny Side Up" by Henderson, Lew Brown, and Buddy G. DeSylva; "Ain't We Got Fun" by Richard A. Whiting, Ray Egan, and Gus Kahn; "Charleston" by James P. Johnson and Cecil Mack; "I'll Get By" by Fred E. Ahlert and Roy Turk; "I've Got a Feeling I'm Falling" by Fats Waller, Harry Link, and Billy Rose; "I Love My Baby (My Baby Loves Me)" by Harry Warren and Bud Green; "A Sailboat in the Moonlight" by Carmen Lombardo and John Jacob Loeb; "Chicago (That Toddlin' Town)" by Fred Fisher; and "Anchors Aweigh" by Charles A. Zimmerman and Alfred Hart Miles. In addition, Dick Hyman composed a number of tunes allegedly inspired by the Zelig phenomenon, including "Leonard the Lizard," "Reptile Eyes," "You May Be Six People, But I Love You," "Doin' the Chameleon," ""The Changing Man Concerto," and "Chameleon Days," the latter performed by Mae Questel, the voice of Betty Boop.
Zelig has the distinction of being the only Warner-released Orion Pictures film that is owned by Orion's successor MGM.
In his review in the New York Times, Vincent Canby observed, "[Allen's] new, remarkably self-assured comedy is to his career what . . . Berlin Alexanderplatz is to Rainer Werner Fassbinder's and . . . Fanny and Alexander is to Ingmar Bergman's . . . Zelig is not only pricelessly funny, it's also, on occasion, very moving. It works simultaneously as social history, as a love story, as an examination of several different kinds of film narrative, as satire and as parody . . . [It] is a nearly perfect - and perfectly original - Woody Allen comedy." 
Variety said the film was "consistently funny, though more academic than boulevardier" , and the Christian Science Monitor called it "amazingly funny and poignant" . Time Out New York describes it as "mildly amusing" , while TV Guide says, "Allen's ongoing struggles with psychoanalysis and his Jewish identity - stridently literal preoccupations in most of his work - are for once rendered allegorically. The result is deeply satisfying."