Affleck's film, about a CIA plot to rescue Americans trapped in Iran from 1979 to 1980, on Sunday won best motion picture drama and claimed the directing prize for Affleck.
The Golden Globes are typically seen as a precursor to the Academy Awards, or Oscars. However, the AP pointed out that Affleck was "surprisingly omitted from the best-director category" in Oscar nominations.
According to CBS, films almost never win Oscars if their directors are not also nominated.
But at the Globes, "Argo" beat out awards-season favorite "Lincoln," which many expect to earn Steven Spielberg an Academy Award on Feb. 24.
The Civil War epic, about Abraham Lincoln's fight for passage of the 13th Amendment abolishing slavery, has 12 Oscar nominations.
However, "Lincoln" did net Daniel Day-Lewis — in the title role — the gong for lead actor in a drama.
Other best director nominees were Ang Lee for "Life of Pi," Kathryn Bigelow for "Zero Dark Thirty" and Quentin Tarantino for "Django Unchained."
If he was hurting over the Oscar snub, Affleck didn't show it, saying in his acceptance speech,"Look, I don't care what the award is. When they put your name next to the names she just read off, it's an extraordinary thing in your life."
The most-honored film of the ceremony, held by the the Hollywood Foreign Press Association at the Beverly Hilton Hotel’s International Ballroom, was "Les Miserables," the musical based on Victor Hugo's classic novel.
It picked up the award for best musical, as well as lead actor and supporting actress wins for Hugh Jackman and Anne Hathaway.
According to the Los Angeles Times, Jackman — aka "Wolverine" — admitted in his acceptance speech that at one point he almost quit the project after a grueling rehearsal.
He thanked his wife for encouraging him to keep going, Australia's Fairfax Media wrote:
"Baby, I’m going to say now in front of the entire world: thank you for always being right."
Hathaway was more upbeat:
"Thank you for this lovely blunt object. I’ll forever use it as a weapon against self-doubt.”
Meanwhile, "Zero Dark Thirty" star Jessica Chastain — who played a CIA agent obsessively pursuing Osama bin Laden — won the Globe for dramatic actress.
In the TV categories, "Game Change" — the made-for-HBO movie about 2008 vice-presidential nominee Sarah Palin, starring Julianne Moore and Ed Harris — and "Homeland," starring Claire Danes and Damian Lewis, won big with three awards apiece.
Witty hosts Tina Fey and Amy Poehler were themselves competing against for best actress in a TV comedy series; Fey for "30 Rock" and Poehler for "Parks and Recreation."
But neither won, with Lena Dunham claiming the comedy series Globe for her hit, "Girls."
She later took to Twitter to describe the experience:
The highlights of my evening (aside from the obvious) were Bill Clinton and Jodie Foster. Also seeing Adele turns out to be like seeingG-d — Lena Dunham (@lenadunham) January 14, 2013