The Hangover star Galifianakis picked up four trophies - including Best Web Personality and Best Online Variety Show - for his comedy internet series, Between Two Ferns with Zach Galifianakis, a cable-show styled skit which appears on FunnyOrDie.com.
Lisa Kudrow, who hosted the ceremony at the Hammerstein Ballroom in New York, was also a winner and picked up her own trophies including Best Individual Performance in an Online Video for her show Web Therapy.
During the evening, the stars had to give their acceptance speeches in just five words, with LCD Soundsystem's James Murphy saying, "Thanks, this is deeply weird", on picking up the Artist Of The Year title.
Other stars noted for their online presence included Funny Or Die co-creator Will Ferrell, who picked up an award for one of his skits on the website, while Justin Bieber won Best Comedy Video for his April Fool's takeover of FunnyOrDie.com.
Arcade Fire also claimed two Webbys for their Wilderness Downtown music video.
The awards were announced in May (11) but the prizegiving ceremony took place on Wednesday and was streamed live on Facebook.com.
Ferrell and screenwriter/director Adam McKay launched the site in 2006, and stars including Charlie Sheen, Sandra Bullock, Lindsay Lohan and Daniel Radcliffe have all filmed spoof videos for the site.
And McKay has now revealed the internet project could explode into cinemas in a movie similar to the Jackass franchise.
He tells Britain's Total Film magazine, "Absolutely (a film), that has been discussed. Paramount released Jackass and we sort of talked about the idea of doing a similar type of movie for Funny or Die. So fingers crossed."
McKay also admits he and Ferrell have snubbed ideas to make a TV series based on the website, adding, "In no way was it a natural progression. You're devolving. Online is so freeform, and all these standards kick in when you go back to television."
"We're just kind of two kindred souls. We were probably brothers in a past life. We just kind of click with our comedic sensibility. It really comes down to the basic thing of thinking the same thing is funny and we totally do. It's the most unique kind of relationship I have with anyone in a way." Funnyman Will Ferrell on pal and Step Brothers co-star John C. Reilly
The Elf star filmed four episodes of the hit sitcom as oddball Deangelo Vickers in place of outgoing actor Carrell, whose final episode as awkward boss Michael Scott aired in America last month (Apr11).
Ferrell recently suggested his run on the show could be extended once producers started looking at the future of the programme, revealing the odds of him becoming a full-time castmember were "looking good".
However, during an appearance on U.S. breakfast show Today on Thursday (12May11), Ferrell admitted he no longer plans to return to The Office.
He said, "I do have to say that the first day on the set and looking at this familiar cast who knows each other very well was slightly intimidating. (But) it's just four episodes and thus far (there are) no plans to come back."
The Anchorman: The Legend of Ron Burgundy star has been chosen by officials at Washington, D.C.'s Kennedy Center for the Performing Arts as the 2011 honouree.
Ferrell will receive the award, named after famed writer Mark Twain, at a glittering ceremony in the U.S. capital later this year (11), and the comedian is delighted with the news.
He tells Variety, "I am truly honoured to receive this distinction. I will now begin cultivating a Mark Twain-esque moustache in anticipation of the event."
Ferrell follows in the footsteps of another former Saturday Night Live (SNL) castmember in receiving the honour - Tina Fey was handed the prize in 2010.
The funnyman stunned fans after signing up to play a lonely office worker alongside Maggie Gyllenhaal in the movie, and admits he loved the experience despite the film's lukewarm reception.
But Ferrell is adamant it would have been more popular had a more serious star signed up for the lead role.
He tells the Wall Street Journal, "I did Stranger Than Fiction and it wasn't like the floodgates opened and I got sent a bunch of serious dramatic roles. I don't think I got sent any...
"I liked that movie a lot, and people recognised it as a nice piece of work. That having been said, what disappoints me is that there's still a stigma attached to the fact that a comedic actor did that role.
"If it was a dramatic actor, I think that movie would have been put on more of a pedestal. I say to Marc Forster, had you cast Russell Crowe you might have gotten more credit as a director. There's an absolute bias."
The two funnymen launched 'Beardpocalypse' last month (Apr11) after Ferrell filmed a video message threat to turn barber the next time he appeared on Conan - and that appearance came on Monday night.
A stern-looking Ferrell quickly raced through pleasantries and promotion for his new movie Everything Must Go, and as O'Brien peppered him with more questions, he yelled, "Would you shut the f**k up? I'm gonna shave that beard. Guys, bring it on, let's go."
A barber's chair was then wheeled out onto the set and Ferrell handed the host a collection of vintage 1970s Playboy magazines, joking, "You're not gonna find anything shaved in there, my friend."
The Elf star then started shaving O'Brien with clippers, adding, "I've only shaved dogs before and I've done some pre-surgery shavings... Just relax, my friend... Just let the blade flow over you."
Ferrell only shaved off half of O'Brien's beard, prompting the host to exclaim, "That's horrible!"
During a commercial break, the host's beard was properly shaved and Ferrell revealed, "I made a terrible mistake," admitting he preferred his friend with a beard.
Organisers of the awards - which celebrate the best of the net - picked pop star Justin Bieber for Best Comedy Video for his April Fool's takeover of Will Ferrell and Adam McKay's FunnyOrDie.com website, in which he re-posted some of his own viral videos.
Friends actress Lisa Kudrow took home two prizes for her show Web Therapy and rock band Arcade Fire claimed two Webbys for the Wilderness Downtown music video.
Late night TV host Conan O'Brien was also honoured for Best Celebrity or Fan Website, while Ferrell and McKay's site nabbed nine of its own.
The prizes will be handed out in a ceremony in New York City on 13 June (11).