Saturday's prize also normally would make Affleck a near shoo-in to win best-director at the Feb. 24 Oscars, since the Directors Guild recipient nearly always goes on to claim the same prize at Hollywood's biggest night.
But Affleck surprisingly missed out on an Oscar directing nomination, along with several other key favorites, including fellow Directors Guild contenders Kathryn Bigelow for "Zero Dark Thirty" and Tom Hooper for "Les Miserables."
Affleck's Oscar snub has not hurt "Argo" and may even have earned it some favor among awards voters as an underdog favorite. "Argo" has dominated other awards since the Oscar nominations.
"I don't think that this makes me a real director, but I think it means I'm on my way," said Affleck, who won for just his third film behind the camera.
The Directors Guild honors continued Hollywood's strange awards season, which could culminate with a big Oscar win for Affleck's "Argo." The guild's prize for best director typically is a final blessing for the film that goes on to win best-picture and director at the Oscars.
Affleck can go only one-for-two at the Oscars, though. While "Argo" is up for best picture, the director's branch of the Academy of Motion Picture Arts and Sciences overlooked him for a directing slot.
Backstage at the Directors
"I'm thrilled and honored that the academy nominated me as a producer of the movie," Affleck said. "I know our movie, we're a little bit underdog and a little bit the little engine that could, and you take me out of it maybe helps ... it's just about that picture. I feel like it's OK, I'm really lucky, I'm in a good place."
With 12 Oscar nominations, Steven Spielberg's Civil War saga "Lincoln" initially looked like the Oscar favorite over such other potential favorites as "Argo," "Les Miserables" and "Zero Dark Thirty," since films generally have little chance of winning best picture if they are not nominated for best director. Only three films have done it in 84 years, most recently 1989's best-picture champ "Driving Miss Daisy," which failed to earn a directing nomination for Bruce Beresford.
But Affleck's "Argo," in which he also stars as a CIA operative who hatches a bold plan to rescue six Americans during the hostage crisis in Iran, has swept up all the major awards since the Oscar nominations. "Argo" won best drama and director at the Golden Globes and top film honors from the Screen Actors Guild and the Producers Guild of America.
Many of the same film professionals who vote in guild awards also cast ballots for the Oscars, so all the wins for "Argo" are a strong sign that the film has the inside track for best picture.
Milos Forman, a two-time Directors Guild and Oscar winner for "One Flew Over the Cuckoo's Nest" and "Amadeus," received the group's lifetime-achievement award. Guild President Taylor Hackford let the crowd in a toast to Forman, who was ill and unable to attend.
Malik Bendjelloul won the guild's documentary award for "Searching for Sugar Man," his study of the fate of critically acclaimed but obscure 1970s singer-songwriter Rodriquez. The film also is nominated for best documentary at the Oscars.
Jay Roach won the guild trophy for TV movies and miniseries for "Game Change," his drama starring Julianne Moore as Sarah Palin in her 2008 vice-presidential run.
Roach said that he watched John McCain rush to choose Palin as his running-mate, potentially putting her second in line for the presidency.
"I said, 'We gotta talk about this,'" Roach joked.
"Girls" star Lena Dunham earned the guild honor for TV comedy, while Rian Johnson won for drama series for "Breaking Bad."
Dunham won for directing the pilot of "Girls," which focuses on the lives of a group of women in their 20s.
"It is such an unbelievable honor to be in the company of the people in this room, who have made me want to do this with my life," Dunham said.
Filmmaker Alejandro Gonzalez Inarritu ("Babel," "Amores Perros") won for best commercial for a Procter and Gamble spot he directed.
Among other TV winners:
— Reality program: Brian Smith, "Master Chef."
— Musical variety: Glenn Weiss, "The 66th Annual Tony Awards."
— Daytime serial: Jill Mitwell, "One Life to Live."
— Children's program: Paul Hoen, "Let It Shine."
Affleck's win Saturday nicks the Directors Guild record as a strong forecast for the eventual directing recipient at the Oscars. Only six times in the 64-year history of the guild awards has the winner there failed to follow up with an Oscar. This will be the seventh, since Affleck is not up for the best-director Oscar.
Peer loyalty might play in Affleck's favor at the Oscars. The acting branch in particular, the largest block of the academy's 5,900 members, might really throw its weight behind "Argo" because of Affleck's directing snub. Actors love it when one of their own moves into a successful directing career, and Affleck—who's rarely earned raves for his dramatic chops—also delivers one of his best performances in "Argo."
Affleck has had no traction in acting honors this season, and he's joked that no one considered it a snub when he wasn't nominated for best actor. So a best-picture vote for "Argo" might be viewed as making right his omission from the directing lineup and acknowledging what a double-threat talent he's become in front of and behind the camera.
A best-picture prize also would send Affleck home with an Oscar. The award would go to the producers of "Argo": George Clooney, Grant Heslov and Affleck.
But it's not as though Affleck has never gotten his due at Hollywood awards before. He and Matt Damon jump-started their careers with 1997's "Good Will Hunting," for which they shared a screenplay Oscar.
AP Entertainment Writer Sandy Cohen contributed to this report.