The series focuses on an eccentric motley crew that is the Smith family and their three housemates: Father, husband, and breadwinner Stan Smith; his better half housewife, Francine Smith; their college-aged daughter, Hayley Smith; and their high-school-aged son, Steve Smith. Outside of the Smith family, there are three additional main characters, including Hayley's boyfriend turned husband, Jeff Fischer; the family's man-in-a-goldfish-body pet, Klaus; and most notably the family's zany alien, Roger, who is "full of masquerades, brazenness, and shocking antics."

The American Dad short film, which preceded the theatrical run of the 2005 feature Fever Pitch, is about Stan Smith touring his work days in the CIA and his "normal" everyday life.