The 37-year-old told The Hollywood Reporter that the show, which has just finished its 10th series, has been running for too long.
“Part of me thinks that Family Guy should have already ended. I think seven seasons is about right,” he said.
The show follows the Griffin family. MacFarlane provides the voice for the dad, Peter.
“I talk to the fans and in a way I’m kind of secretly hoping for them to say we’re done with it,” he said.
“There are plenty of people who say the show is kind of over the hill, but still the vast majority go pale in the face when I mention the possibility.”
The writer, who is also responsible for other US cartoons including American Dad and The Cleveland Show, said he would prefer to end the show and release a film every few years.
There is a deal in place for a Family Guy movie, which MacFarlane is reported to be writing along with series co-producer Ricky Blitt.
He is also set to bring back a revamped version of 1960s Hanna-Barbera cartoon The Flintstones.
When he made the announcement in May, MacFarlane revealed Fred Flintstone had been “the very first cartoon character I drew at age two”.