The Sheen roast is to air on the cable network Sept. 19.
"I'm very excited to work with Comedy Central again on the roast," writer-actor-producer MacFarlane said in a statement Thursday. "Charlie is a true icon with a talent that is strong and pure and concentrated into small crystals which can be smoked or eaten."
"In addition to his sharp wit, Seth is way more suave and sophisticated than we are. We continue to try and soil him," added Comedy Central programming head Kent Alterman.
MacFarlane has previously emceed ceremonies starring Donald Trump and David Hasselhoff and is the franchise's only three-time roast master.
Sheen was fired this year from the sitcom "Two and a Half Men" after eight seasons because of his erratic behavior and substance abuse, as well as for disparaging remarks he made about series creator Chuck Lorre. He later announced he is planning to star in a comedy series inspired by the film "Anger Management."