Twitter came alive with praise for MacFarlane, while 57.1% of those who took part in a real-time poll on TVline.com rated his debut "above average" or even "awesome" at the outset of a musically-themed Oscar evening.
Star Trek star William Shatner, in the role of Captain James Kirk, literally dropped in from the future to warn MacFarlane he was doomed to be the "worst Oscars host ever".
Twitter trends
The monologue veered into frat house humor with We Saw Your Boobs, a 1930s song-and-dance number with MacFarlane name-checking actresses - many in the audience - who've appeared nude on screen in their careers.
The real-life Gay Men's Chorus of Los Angeles joined the production number, and #wesawyourboobs briefly trended on Twitter.
Take a look at Seth MacFarlane's opening song.
Prompt relief came from sock puppets re-enacting the crash scene from Flight before MacFarlane returned as the Flying Nun in a flirty green-room encounter with Sally Field, the original Sister Bertrille in the 1960s TV show.
Tough crowd to please
But not everyone was impressed.
"Seth McFarlane is wearing a tuxedo made of self-satisfaction and irrelevant pop culture references," TV writer Ed Lee tweeted during the ceremony.
Later on, MacFarlane tested the margins of good taste with a reference to Daniel Day-Lewis's Oscar-nominated performance as Abraham Lincoln in Steven Spielberg's eponymous film.
"The actor who really got into Lincoln's head was John Wilkes Booth," said the comedian, referring to the Civil War president's assassin.