After six months, MacFarlane returned to Fox with a "very, very simply, crudely animated film – with just enough to get the tone of the show across" to present to the executives, who loved the pilot and ordered the series immediately. In July 1998, the Fox Broadcast Company announced the purchase of Family Guy for a January 1999 debut. Family Guy was originally intended to be a series of shorts on MADtv, much in the same way The Simpsons had begun on The Tracey Ullman Show a decade earlier. Negotiations for the show's MADtv connection fell through early on as a result of budgetary concerns. At age 24, MacFarlane was television's youngest executive producer.

Family Guy first aired January 31, 1999. MacFarlane's work in animating Family Guy has been influenced by Jackie Gleason and Hanna-Barbera along with examples from The Simpsons and All in the Family.In addition to writing three episodes, "Death Has a Shadow", "Family Guy Viewer Mail 1" and "North by North Quahog", MacFarlane voices Family Guy's main characters – Peter Griffin, Stewie Griffin, Brian Griffin and Glenn Quagmire as well as Tom Tucker, his son Jake and additional characters. Bolstered by high DVD sales and established fan loyalty, Family Guy developed into a $1-billion franchise.