Debicki beat The Morning Show's Jennifer Aniston, The Last of Us' Bella Ramsey, The Diplomat's Keri Russell and Succession's Sarah Snook.
"Truly, I was not expecting this," the 33-year-old said. "The women in my category, I watch with total awe and I learn how to do my craft watching you. So being nominated next to you is incredible."
Earlier Irish star Cillian Murphy won best male actor for his role in Oppenheimer.
Robert Downey Jr and Da'Vine Joy Randolph each won for their supporting performances, likewise solidifying their status as Oscar favourites.
Downey Jr., accepting his first SAG Award for a movie role in Christopher Nolan's Oppenheimer, grinned as he accepted the trophy.
"Why me? Why now? Why do things seem to be going my way?" said Downey Jr.
"Unlike my fellow nominees, I will never grow tired from the sound of my own voice."
The Bear stars Jeremy Allen White and Ayo Edebiri won best actor and actress in a television comedy respectively for their roles in the show about a gourmet chef trying to turn around his family's Chicago sandwich shop.
Ali Wong was named best actress in a limited series for road rage drama Beef. She thanked her 83-year-old mother who was in the audience.
"I know it was really hard when I told you I wanted to do stand-up comedy, and I hope you feel like it all worked out," she said.
Blockbuster movies Barbie and Oppenheimer were facing off again for the night's top award of best motion picture cast. Others in the running are The Color Purple, Killers of the Flower Moon and American Fiction.
Barbie stars America Ferrera and Margot Robbie during the 30th annual Screen Actors Guild Awards. (AP PHOTO)
SAG-AFTRA's film choices are closely watched because actors form the largest group of voters for next month's Academy Awards, the film industry's top prizes.
A win for director Christopher Nolan's historical drama Oppenheimer would bolster its frontrunner status for best picture at the Oscars. The movie about the race to build the first atomic bomb has picked up top prizes at the Golden Globes, the British Academy Film Awards and other ceremonies.
Barbra Streisand was honored with the SAG Life Achievement Award in recognition of her prolific career and humanitarian work.
The 81-year-old Streisand received SAG's highest award from Jennifer Aniston and Bradley Cooper. She was the 59th recipient of the award, which goes to an actor who fosters the "finest ideals of the acting profession." She was received with a standing ovation and many actors in tears.
Streisand recounted her dream of becoming an actress as a teenager in Brooklyn and being in awe of actor Marlon Brando in the 1955 film Guys and Dolls.
"That make-believe world was much more pleasant than anything I was experiencing," she told the crowd.
"I didn't like reality. I wanted to be in the movies even though I knew I didn't look like the other women on the screen. My mother said, 'You better learn to type,' but I didn't listen."
