Cherie Johnson is the niece of the show's creator and producer, David W. Duclon, who named the character for her. Nevertheless, she auditioned for the role like everyone else and was picked by the network to play the part.
Then-NBC programming chief Brandon Tartikoff helped develop the show, naming Punky Brewster after a girl he had a crush on in school. The real Punky Brewster was married to a lawyer in Connecticut and received a royalty check to use her name. She made a cameo appearance in one episode as Punky's teacher.
Melissa Joan Hart originally auditioned for the part of Punky Brewster. Coincidentally, Soleil Moon Frye, who got the part, later co-starred with her on Sabrina the Teenage Witch (1996).
Fred Gwynne was originally cast to play Henry but backed out when, in an audition for the role of Henry P. Warnimont, he was identified as Herman Munster, which was his role on The Munsters (1964).
Because several episodes were scheduled to air after football games, which sometimes ran overtime; six 15-minute episodes were aired. This was to accomodate young viewers being able to watch the episodes and still be in bed early.