"Birdman," a satire of show business that led all nominees with seven nods, picked up best screenplay and best actor in a comedy or musical for Michael Keaton, embodying a comeback in film and real life.
"Alejandro, there is not a person in this room who won't show up for your next gig," said Keaton of "Birdman" director Alejandro Inarritu.
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But "The Grand Budapest Hotel" from director Wes Anderson was the big surprise of the night as best comedy or musical, although it only took home that one award.
Civil rights drama "Selma" won one award, for best song, while "The Imitation Game" walked away empty-handed.
The outcome of the 72nd Globes will not influence the Academy Awards slate, since voting for next week's nominees announcement is closed. But it can give crucial momentum to the Oscar race.
Other top actor awards went to performers who portrayed the pain of illness.
Julianne Moore won best actress in a drama as an early-onset Alzheimer's patient in "Still Alice," while Eddie Redmayne took best actor in a drama for his portrayal of physicist Stephen Hawking in "The Theory of Everything."
It was a more somber night than usual for the Golden Globes, usually one of the more rambunctious events in the awards season, organized by the Hollywood Foreign Press Association.
Politics played heavily into acceptance speeches, from support for the Hispanic and transgender communities to calls to protect freedom of expression and solidarity after the deadly attack on French satirical newspaper Charlie Hebdo.
George Clooney, receiving a lifetime achievement award and sporting a lapel pin declaring "Je suis Charlie," noted the "extraordinary day" in Paris and around the world as millions of people and world leaders marched to pay tribute to victims of Islamist militant attacks.
"They marched in support of the idea that we will not walk in fear," said Clooney. "Je suis Charlie."