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 precedes before the theatrical run of the 2005 feature Fever Pitch; is about Stan Smith touring his work days in the CIA and his "normal" every day life.