The funnyman served as the guest host of the hit TV programme and introduced himself to viewers by showing off his most recognisable talent, his voice, as he pretended to speak as Family Guy's Peter Griffin, Stewie and Quagmire in the opening monologue of the 38th season.
He also shared an original musical number, titled My Head is Full of Voices, as he impersonated Star Trek's George Takei, Michael J. Fox's Back to the Future character Marty McFly and Kermit the Frog, much to the audience's delight.
However, not all of MacFarlane's gags got laughs - an uncomfortable silence fell over the studio audience as he referenced the late Farrah Fawcett, who lost her battle with cancer in 2009.
He said, "I've loved the show since I was a kid and I promised myself there was one thing I would do if I ever got to host, so just indulge me for a moment - please go out with me, Farrah Fawcett. OK, I guess I made that promise a while ago..."
Meanwhile, show regular Bill Hader poked fun at Clint Eastwood's bizarre empty chair speech at America's Republican National Convention last month (Aug12) by posing as the Dirty Harry icon, and South Korean dance sensation Psy made a surprise appearance to show off his horse-inspired moves with the cast of Saturday Night Live.
R&B star Frank Ocean provided the music and took the stage with John Mayer on guitar as he performed two tracks on the show. The rocker didn't utter a word the entire set - he is on voice rest for six months following an operation on his throat in August (12).