Last year, Inarritu won the same award for "Birdman" and went on to win three Oscars for best picture, original screenplay and director.
An emotional Inarritu fought back tears on accepting the trophy from "The King's Speech" director Tom Hooper.
"I never expected to win this award, truly. I'm paralyzed. Tough men don't cry, that's what Ridley Scott said today," Inarritu said.
Inarritu also slammed Donald Trump backstage for his proposal to build a wall on the US Mexico border.
Inarritu saw off competition from Tom McCarthy for "Spotlight," Adam McKay for "The Big Short," George Miller for "Mad Max: Fury Road" and Ridley Scott for "The Martian."
The DGA win places "The Revenant" in the role of favorite for the directing Oscar.
Inarritu has joined a select group of directors who have won the DGA trophy twice including Ang Lee, Francis Ford Coppola, Clint Eastwood, George Stevens, David Lean, Ron Howard and Joseph Mankiewicz.
Steven Spielberg is the only director to have won the DGA feature trophy three times.
Dee Rees won the TV movie-miniseries award for "Bessie," the biopic of pioneering blues singer Bessie Smith.
Nutter, Addison and Reese were first-time winners.
Matthew Heineman won the documentary award for "Cartel Land," centered on the Mexican drug war.
"Cartel Land" topped "Amy," "Going Clear: Scientology and The Prison of Belief," "Meru," and "What Happened, Miss Simone?"
"Amy," "Cartel Land" and "What Happened, Miss Simone" have each received Oscar nominations.
Garland directed "Ex Machina" from his own script. The film, which stars Alicia Vikander as an android, topped Fernando Coimbra for "A Wolf at the Door," Joel Edgerton for "The Gift," Marielle Heller for "The Diary of a Teenage Girl" and Laszlo Nemes for "Son of Saul."
Kenny Ortega won the children's award for "Descendants."
Andreas Nilsson of Biscuit Filmworks won the commercials award. Adam Vetri won the reality TV award for "Steve Austin's Broken Skull Challenge.
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