Lynne Marie Stewart, who plays Jimmy, the snake farm owner, was Miss Yvonne in the original Pee-wee's Playhouse (1986) TV series.
Along with wearing makeup and using tape on his face, visual effects were used to "de-age" Paul Reubens's face. The Pee-wee films and the television series were used as references.
This is the first Pee-wee Herman film in 28 years.
The female bank robbers are patterned after Varla, Rosie and Billie from Russ Meyer's cult classic Faster, Pussycat! Kill! Kill! (1965).