Both shows air on Fox, and the news comes after MacFarlane featured Dan Castellaneta, the voice of Homer Simpson, in a recent "Family Guy" episode.
MacFarlane, 39, also created and voices characters for animated comedies "American Dad" and "The Cleveland Show," and he had a box-office hit with R-rated comedy "Ted" this past summer.
He will be hosting the Oscars in February.
"The Simpsons" first aired in 1989 and is now the longest-running US sitcom in history and is broadcast in more than 100 countries.
The show has seen a diverse range of guest stars across all spectrums of pop culture including Bill Clinton, Buzz Aldrin, Tony Blair, Julian Assange and Lady Gaga.