The 37-year-old "Jobs" star, married to Mila Kunis, who voices the character Meg Griffin on the show, will guest-star as himself in a live-action short, reported Entertainment Weekly.
"We wrote him some of the most ridiculous dialogue. He just couldn't have been a nicer guy or a better sport about it," executive producer Steve Callaghan said.
Mellencamp, 63, will also play an animated version of himself and perform an original song in the season premiere.
Margaret Cho, Kyle Chandler, Kathryn Hahn, Jeff Garlin and astrophysicist Neil deGrasse Tyson will also voice characters on the next season of Seth MacFarlane's hit animated series.
"Family Guy" will premiere on September 27 on Fox.
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