The musical "Nine" ran second with five nominations, including best musical or comedy and acting slots for Daniel Day-Lewis, Penelope Cruz and Marion Cotillard.
Also competing for musical or comedy are the romance "(500) Days of Summer," the bachelor-party bash "The Hangover" and two Meryl Streep films, "It's Complicated" and "Julie & Julia."
"Up in the Air" generally has been considered a comedy, but its inclusion in the drama category could give it more weight as a potential favorite for the Academy Awards, where dramatic films tend to dominate. The film also earned best-director and screenplay nominations for Jason Reitman.
Playing a frequent-flyer junkie in "Up in the Air," Clooney had a nomination for best dramatic actor, along with Jeff Bridges as a boozy country singer in "Crazy Heart," Colin Firth as a grieving gay academic in "A Single Man," Morgan Freeman as Nelson Mandela in "Invictus" and Tobey Maguire as a prisoner of war in "Brothers."
Streep had two nominations for musical or comedy actress, as chef Julia Child in "Julie & Julia" and a woman in an affair with her ex-husband in "It's Complicated."
Sandra Bullock also had two nominations, as dramatic actress in the football story "The Blind Side" and as a dragon-lady boss forcing her assistant to pose as her fiance in "The Proposal."
Matt Damon picked up two nominations, as well, as musical or comedy actor playing a whistleblower spinning wild fabrications in "The Informant!" and as supporting actor playing a South African rugby star in "Invictus."
Other dramatic actress nominees were Emily Blunt as Britain's monarch in her early reign in "The Young Victoria," Helen Mirren as the imperious wife of Leo Tolstoy in "The Last Station," Carey Mulligan as a 1960s British teen in an affair with an older man in "An Education" and Gabourey Sidibe as an illiterate, abused teen turning her life around in "Precious."
Julia Roberts was a surprise nominee for musical or comedy actress as a corporate spy in "Duplicity," a box-office underachiever that generally was not on the awards radar. Along with Roberts, Streep and Bullock, Cotillard rounded out the category as the wife of an unfaithful filmmaker in "Nine."
Day-Lewis as the "Nine" filmmaker scored a nomination for musical or comedy actor. Besides Damon, the category also includes Robert Downey Jr. as the London detective in "Sherlock Holmes," Joseph Gordon-Levitt as a lovesick man in "(500 Days of Summer" and Michael Stuhlbarg as a 1960s Jewish academic besieged by crises in "A Serious Man."
"Up in the Air" co-stars Farmiga, playing Clooney's frequent-flyer soul mate, and Anna Kendrick, playing a smart but inexperienced efficiency expert, are competing against each other for supporting actress. Also nominated are Cruz as the filmmaker's insecure mistress in "Nine," Mo'Nique as a hateful welfare mother in "Precious" and Julianne Moore as a grief-stricken professor's best pal in "A Single Man."
Damon is joined in the supporting-actor category by Woody Harrelson as a military man delivering bad news to next of kin in "The Messenger," Christopher Plummer as aging author Tolstoy in "The Last Station," Stanley Tucci as a serial killer in "The Lovely Bones" and Christoph Waltz as a gleefully savage Nazi in "Inglourious Basterds."
Hollywood's second biggest film honors after the Academy Awards, the Globes are a key ceremony that sort out the prospects leading up to the Oscar nominations Feb. 2.
The 67th annual Globes will be handed out Jan. 17, six days before nomination voting closes for the Oscars. Globe winners can get a last-minute bump for an Oscar nomination, particularly on smaller films such as 1999's "Boys Don't Cry," whose Globe triumph for Hilary Swank helped put her on the map for a best-actress win at the Oscars.
Last year's best drama winner at the Globes, "Slumdog Millionaire," went on to win best picture and dominate at the Oscars. Other Globe recipients who followed with Oscar wins included Heath Ledger as supporting actor for "The Dark Knight" and Kate Winslet, who won supporting actress at the Globes for "The Reader" and best actress for that film at the Oscars.
The Globes are presented by the Hollywood Foreign Press Association, a group of about 85 critics and reporters for overseas outlets.