Will Smith refused to actually kiss Anthony Michael Hall just before their kissing scene so a camera trick was used showing only the back of their heads. In an interview, Smith stated that Denzel Washington advised him not to kiss a man on-screen for it would harm his career. Smith stated that he regretted not going through with it saying "It was very immature on my part."
Will Smith's character in the film passes himself off as Sidney Poitier's son. In real life, when Smith met Poitier for the first time, the veteran actor said "Well, you're almost handsome enough to be my son".
When Paul is talking about his thesis, he mentions the Lord of the Rings books. Geoffrey, who is listening to him, is played by Ian McKellen, who almost a decade later played Gandolf in the Lord of the Rings films.
To make the movie acceptable for TV showings, the nude hustler (Lou Milione), has been digitally altered. In the scene after he is discovered with Paul (Will Smith), he is chased around the apartment. In the original version, he is completely naked. But in the TV version, white jockey underwear has been added digitally.
Doug (J.J. Abrams), when looking through the yearbook with the other college children, exclaims "remember Greg Grunberg?", a reference to Abrams' childhood friend whom he often casts in his own projects.
J.J. Abrams, who played Doug, went on to become a writer and producer of several television shows, including one called Six Degrees (2006) (a reference to the same "small world" theory that is discussed in Six Degrees of Separation (1993).
The original Broadway production of "Six Degrees of Separation" opened at the Vivian Beaumont Theater on November 8, 1990, ran for 485 performances and was nominated for the 1991 Tony Award for Best Play. Stockard Channing reprises her role in the movie while her fellow Broadway stage actors Kelly Bishop, John Cunningham and Sam Stoneburner have cameo roles. Stockard Channing was nominated for the 1991 Tony Award for Best Actress in a Play. John Guare wrote both the stage play and the screenplay for the movie adaptation.
L.A. Theatre Works produced a radio adaptation of the play, in which Ouisa and Flan are played by Swoosie Kurtz and Alan Alda. Alda, of course, became famous for taking over another role from Donald Sutherland: "Hawkeye" Pierce from M*A*S*H (1972).