Santo Bugito is set in a titular border town between Texas and Mexico, populated by various anthropomorphic insects. Carmen De La Antchez (Marabina Jaimes) is the show's protagonist, an ant who runs a restaurant in the town with her husband, Paco (Tony Plana). The town is populated by other insects, including two brash American flies, Clem (William Sanderson) and Burt (Michael Stanton), a hyperactive flea named Lencho (Cheech Marin), a cynical artist termite named Eaton Woode (Charles Adler), a butterfly named Rosa (Candi Milo) and her boyfriend Miguel who is still in his cocoon, Amelia (Joan Van Ark), an enthusiastic damselfly, Ralph, a large friendly ladybug with a deep voice (George Kennedy) and a praying mantis professor who occasionally interrupts the show to give dull educational lectures, but is usually pushed off-screen by another character. The show primarily deals with slice of life stories, but often with a strange insect twist. Some episodes include the town still trying to operate when Carmen is bedridden with a broken leg ("The Carmen Tango"), Lencho trying to attract a famous black widow spider dancer to perform in the town ("A Widow Goes a Long Way"), and one where a mosquito lawyer named Emma Squito comes to town, and everyone in the town is caught up in a suing frenzy, in exchange for Emma sucking the blood from each of her clients ("Sue City"). A mariachi band of ants occasionally narrate the action with music.