Though MacFarlane is the comic genius behind the wildly popular animated TV shows, "Family Guy," "The Cleveland Show" and "American Dad," as well as this past summer's raunchy blockbuster comedy "Ted," he remains a relative outsider to Hollywood.
That makes him both appealing and unpredictable.
"If it's too soft I'm going to disappoint a lot of my fan base, if is too hard I'm going to lose that room," MacFarlane told ABC News' Barbara Walters in December about the balance he'll try to strike this Sunday, when the 85th Academy Awards is presented live on ABC.
MacFarlane revealed on "Good Morning America" Thursday that nothing -- and no one -- will be off-limits to him as possible targets for jokes.
And, if initial reaction to the cracks he made while announcing the Oscar nominees last month is any indication, audiences could be in for a wild ride.
"In the less than 10 minutes it took to announce the nominees, MacFarlane managed to insult his co-presenter, belittle the achievements of several nominees and make a Hitler joke," Slate wrote.
Though MacFarlane often pushes the boundaries of the TV censors for his animated shows, the 39-year old promises the jokes on Sunday will still be family friendly -- to an extent.
"The Oscars will still be something a family in 2013 can sit down and watch and be just fine with," he told USA Today earlier this week. "A family in 1955 might have some issue with it. In 2013, everyone will be fine. Then again, I'm not married and I don't have kids. And my mother was saying (nasty things) out loud by the time I was 5. So maybe I'm the wrong guy to ask."
"The Oscars have been criticized for seemingly not being relevant, and that goes to our choice of Seth," producer Neil Meron told USA Today. "He's a reflection of the current pop culture and completely relevant. We love that."
MacFarlane's already demonstrated his hosting chops with Comedy Central roasts of David Hasselhoff, Donald Trump and Charlie Sheen. He's the only host to be asked back again. Don't expect him to repeat at the Oscars, though. He's already declared this a one-off gig.
Asked by "GMA" what superlative he thought would be used to describe his job as host, MacFarlane responded, "Gosh, I don't know -- most astonishingly dazzlingly mediocre?"
If you still have no clue who he is, we've made a list of seven things you should know about Seth MacFarlane ahead of Sunday's Academy Awards.
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quicklist: title: 1. He's a Prodigy text: "I was a combination of reclusive and obsessed with what I wanted to do," MacFarlane told Walters after being chosen as one of her "10 Most Fascinating People" of 2012. "When I was 2, I was sitting in front of the TV set drawing Fred Flintstone and Woody Woodpecker."
Raised in Kent, Conn., the son of ex-hippies-turned-teachers, MacFarlane started doing a comic strip for his local paper at age 9. In seventh grade, he made his first animated cartoon, "Space Pirates" -- "It was terrible," he said. Later, at the Rhode Island School of Design, he performed in student films and made some of his own, including the animated "The Life of Larry," which became the seed for "Family Guy."
quicklist: title: 2. He Made History text: At age 24, MacFarlane made history as the youngest person to ever head a network show as the mastermind of "Family Guy."
MacFarlane produces, writes and even oversees the music for the show. He also voices four of the characters, including 11-month-old Stewie Griffin, his blue-collar dad Peter Griffin and their dog Brian.
The show is equal parts juvenile, profane and warm-hearted, tackling everything from bestiality to flatulence. MacFarlane told Walters the trick to getting his material past the censors is to not offend too many groups in any one episode.
"It all can't be in the same place," he said. "There's something called tonnage. We try to keep those jokes spread apart. It is a balance. But my view is, if it makes you laugh, it's an honest laugh."
quicklist: title: 3. He Narrowly Escaped Death on 9/11 text: MacFarlane had been scheduled to fly on the doomed American Airlines flight from Boston that was hijacked by terrorists and deliberately crashed into the World Trade Center on Sept. 11, 2001.
Instead, he arrived late at the airport -- after partying hard the night before and getting the departure time wrong -- and missed the flight. "I was generally late for flights," MacFarlane told Piers Morgan in 2011. "In that moment, we're all the same. I'm not a fatalist. I was not shaken to the core."
Ironically, MacFarlane's "Ted" co-star Mark Wahlberg had also been scheduled for Flight 11 but canceled his ticket at the last minute.
quicklist: title: 4. He's a (Frugal) Millionaire text: MacFarlane is said to be worth $30 million, and the "Family Guy" franchise, which includes "The Cleveland Show" and "American Dad," is valued over $2 billion, but the comiedian says he does not make a lot of "frivolous purchases."
"The only thing in the past 10 years that could be considered extravagant is I bought a time share in a plane," he told Walters. "It's nice to be able to avoid the airports, but that's about it."
Asked why he didn't buy the entire plane, he quipped, "Oh Lord no, I'm not Bill Gates."
quicklist: title: 5. His First Film Was a Smash text: MacFarlane only recently joined the ranks of Hollywood, when he wrote and directed his first film.
"Ted," released last summer with Mark Wahlberg and Mila Kunis -- and MacFarlane as the voice of the profane teddy bear, Ted -- is the highest-grossing R-rated comedy of all time.
In addition to hosting Sunday, MacFarlane has a chance at winning an Oscar. He received a nomination for the movie's theme song, which he co-wrote and Norah Jones sings in the film. Jones is also scheduled to perform for Sunday's telecast.
He told "GMA" that he was "genuinely excited" about the nomination, but added, "I know we're going to lose to Adele … ."
quicklist: title: 6. He's a Song and (Not Quite) Dance Man text: You've probably figured out by now that MacFarlane is a musical man.
In September 2011, he released an album of American standards called "Music is Better Than Words."
So, yes, he's planning to sing at the Oscars.
"You've got a 60-piece orchestra there. It's just too big a temptation not to use," he told Walters.
And though he's admitted he's no dancer, you can expect to see him bust a move.
The show's producers announced Thursday that MacFarlane and Kristin Chenoweth will close the show Sunday with a musical performance. "We think it will be a 'can't miss' moment," the show producers Craig Zadan and Neil Meron said in a statement.
quicklist: title: 7. He's Not Afraid of Little Controversy text: The big question is how far will MacFarlane go? Will he go as far as Ricky Gervais at the 2011 Golden Globes?
MacFarlane has already shown he's not afraid of a little controversy. During Emmy voting in 2012, his mailer to voters for "Family Guy" included the phrase "Come on, you bloated, overprivileged Brentwood Jews. Let us into your little club."
As expected, controversy erupted, with MacFarlane telling E! News, "Hollywood is a town of very well-to-do folks who live very comfortably. They have a very comfortable lifestyle, they do what they love, there's not much that is bad in their life. So they should be able to laugh at themselves. If they can't, it's a rather sad thing."
Let's see if he makes them laugh Sunday.