NBC programming chief Brandon Tartikoff named the series after a girl he had a childhood crush on, an older tomboy named Peyton "Punky" Brewster. Before the show aired, NBC tracked her down and secured her permission to use her name for the lead character.

The real Peyton Rutledge was hired for a cameo as a teacher in the episode "The Search" (aired November 10, 1985), so that both the real and fictional Punky Brewster could appear on screen together, with the teacher remarking "Punky Brewster? Strange name!"

Punky's dog Brandon was named after Brandon Tartikoff himself; the dog's real name was Sandy, who originally shared the role with his brother until Tartikoff decided Sandy was better suited for the part.

Because the show had many young viewers and aired on Sundays after football games that often ran long, six special fifteen-minute episodes were produced so the network could air a complete short episode instead of joining a full-length one already in progress.

The second season finale centered on the real-life Space Shuttle Challenger disaster, showing Punky traumatized after watching the launch live in class; her teacher Mike then brought in former NASA astronaut Buzz Aldrin to visit her.

The final episode, "Wedding Bells for Brandon," was not originally intended to be the series finale, but became so because it aired amid the 1988 Writers Guild of America strike, according to Cherie Johnson.

The season 1 finale "Fenster Hall" was a one-hour crossover episode intended as a backdoor pilot for a spin-off series starring T. K. Carter as Mike Fulton, but the spin-off never materialized after NBC's 1985–86 upfronts, so Carter's character instead became a regular teacher on Punky Brewster the following season.

Because NBC was barred by FCC regulations from co-producing the show once it moved into syndication, the network struck a deal with Coca-Cola Telecommunications to co-produce two additional syndicated seasons.