It revolves around a dysfunctional family known as the Griffins. The family, who resides in Rhode Island, in the non-existent city of Quahog, consists of overweight, bumbling patriarch Peter; his wife Lois, unfortunate daughter Meg, oldest son Chris, youngest son Stewie – a Rex Harrison-esque talking infant, originally a diabolical child-genius obsessed with world domination and matricide, but in recent years, has become more of an eccentric, sexually ambiguous character – and anthropomorphic dog Brian.
References to Peanuts
- Charlie Brown appears in the episode "E. Peterbus Unum". When the characters are saying what they got with their tax return, Charlie Brown, dressed unconvincingly as a ghost, says "I got a rock" (referring to It's the Great Pumpkin, Charlie Brown).
- Peter repeats Linus' request of "Lights please." from A Charlie Brown Christmas in "A Very Special Family Guy Freakin' Christmas".
- During the Logan's Run dream in "Brian in Love", Brian points out to the guards that another dog, who looks like Snoopy, has "gotta be in his 50s."
- In "Road to Europe", Brian compares Stewie to Charlie Brown and Stewie compares Brian to Snoopy.
- In "Lethal Weapons", Lucy pulls away a football as Lois tries to kick it. Lois then kicks her in the face and she cries.
- In the episode "Ready, Willing, and Disabled", Stewie groans like Charlie Brown when his sibling takes his money. His face becoming nothing but a wide open mouth, and he says "Aughh".
- Peter visits adult versions of Peppermint Patty and Marcie, depicted as lesbians, in "Stuck Together, Torn Apart".
- Peter claims he has to destroy Mel Gibson's film The Passion of the Christ 2: Crucify This in "North by North Quahog" for the good of Snoopy and all of the other children's characters.
- In "Brian Goes Back to College", Brian is kicked out of the offices of The New Yorker, in a reference to Snoopy being kicked out of public buildings and kicked off public transportation in the Peanuts movie, Snoopy Come Home. To complete the Peanuts motif, Brian then walks over to a doghouse resembling Snoopy's, climbs onto the roof and lies there as jazzy Peanuts-esque music plays.
- Charlie Brown appears in a flashback in "Mother Tucker", grown up and behaving abominably at the Peanuts reunion where his guest is a coarse skanky crackwhore. He breaks down in tears because Snoopy and Woodstock are dead, the strong implication being that he supplied the drugs which led to their demise. He makes things worse by claiming that he does not care about Woodstock, but that Snoopy did not deserve to die.
- In "No Meals on Wheels", Violet and "Pig-Pen" see Stewie running Lucy's psychiatry booth.
- In "Love, Blactually", both Brian and Stewie dress as Snoopy for a costume party. Brian even mimics Snoopy's dance for Peter, who subsequently punches him in the gut. Brian is followed by Woodstock after deciding not to go out with Jane.
- Lucy van Pelt appears, pulls away a football from Charlie Brown and is kicked by Peter making her cry in "Brian's Got a Brand New Bag".
- When Stewie tells Chris that he cannot always get things right in "Turkey Guys", he sets up a cutaway of Snoopy's "original "Happy Dance"" in which Snoopy does a bump and grind against Lucy.