He was handed the accolade for his portrayal of stammering King George VI in The King's Speech, boosting his chances of an Oscar nomination later this month.
There was also success for Welsh actor Christian Bale, who took home the supporting actor gong for his role in The Fighter at the Los Angeles awards ceremony.
British hopes had been pinned on The King's Speech, which tells the story of the unlikely relationship between the monarch and an Australian speech therapist who helps him cope with his stammer.
It was nominated in seven categories, but Firth's award was the only one it picked up on the night.
Ricky Gervais was back for a second year as host of the aeards, and he poked fun at A-list stars, blockbuster movies and even awards' bosses.
"It's going to be a night of partying and heavy drinking," Ricky began his monologue, sipping from a glass of what looked like beer. "Or, as Charlie Sheen calls it, breakfast."
He then made a jibe at the expense of nominated film The Tourist.
"I feel bad about that joke," he said after his first dig. "I'm jumping on the bandwagon, because I haven't even seen The Tourist. Who has?"
He was just warming up. He went on to tell the audience that The Tourist had not been nominated by the Hollywood Foreign Press Association just because its members wanted to hang out with the film's stars, Johnny Depp and Angelina Jolie. "That is not the only reason," Gervais insisted with a saucy smile. "They also accepted bribes."
Having already bitten the hand that was feeding him, Ricky soon bit the HFPA's other hand.
He announced that Eva Longoria would be on next with "the daunting task" of introducing Philip Berk, the association's president. "That's nothing," Gervais added. "I just had to help him off the toilet and pop his teeth in."
Ricky's jokes received a mixed response from his audience. "Ricky Gervais will not make it out of town tonight," film producer Harvey Weinstein joked at the Weinstein after-party.
The King's Speech director Tom Hooper laughed: "I thought he was hilarious but will he ever present another award show again? I don't know but if he went out, he went out burning."
Actor Ryan Gosling was on the comedian's side. "He's the best, Ricky Gervais can do no wrong!" he insisted.
Accepting his award, Firth referred to his age and said: "To get to this stage of your life with your dignity and judgment intact can be somewhat precarious. Sometimes all you need is a bit of gentle reassurance to keep you on track but right now this (the award) is all that stands between me and a Harley Davidson."
His co-star Helena Bonham Carter said she did not mind missing out in the best supporting actress category to The Fighter's Melissa Leo.
She said: "I'm really glad Colin won, it was fine. I was so glad I didn't have to get up and give a speech."
The actress admitted she was not too upset The King's Speech missed out to The Social Network for best picture.
She said: "At the time you're just glad you don't have to get up. I'm slightly split because I really like David Fincher (who won the best director award for The Social Network) because I've worked with him, but whatever, all I care about is if I'm going to get another job, that's all it's about."
The King's Speech director Tom Hooper was equally gracious in defeat.
"I'm thrilled for Colin, I was just pleased to be in the room with seven nominations in the first place," he said.
Hooper said Firth's reference to a possible mid-life crisis was a joke and, referring to his Golden Globe nomination for A Single Man last year, said he would cope with the spotlight.
He said: "Look, he's done the whole thing before and it was only a year ago.
"I think he has his way through and he has his lovely wife Livia, his great supporter, and he's got all of us."
Co-star Guy Pearce, who plays King Edward VIII in the film, said he was thrilled to see Firth recognised.
He said: "I'm more than pleased for Colin tonight. How could one be more excited for such a lovely and talented man to win an award such as this? I think for Colin, particularly, he delivered such a great performance - it's fantastic."
In his acceptance speech, Batman star Bale paid tribute to Mark Wahlberg, his co-star in The Fighter.
"I've really got to give a shout-out to Mark, because he drove this whole movie, and you can only give a loud performance like the one I gave when you have a quiet anchor and a stoic character," he said.
"I've played that one many times, and it never gets any notice."
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