LIST | See the full list of Oscars winners here
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He had previously been nominated for Best Actor for "Chaplin" in 1993,and for Best Supporting Actor in 2008 for "Tropic Thunder"
In "Oppenheimer," Downey plays Atomic Energy Commission head Lewis Strauss, a key figure in the the United States' effort to build and later deploy a nuclear weapon towards the end of World War II.
READ MORE: Who was the real Robert Oppenheimer, played by Cillian Murphy?
Downey gave a light-hearted speech as he accepted his award.
"I'd like to thank my terrible childhood" he said, pausing for the audience's laughter, "and the academy, in that order."
He also thanked his wife, Susan. "You loved me back to life and that's why I'm here."
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Downey beat Sterling K. Brown for "American Fiction," Ryan Gosling for "Barbie," Mark Ruffalo for "Poor Things" and Robert De Niro for "Killers of the Flower Moon."
Recently, Downey came away with awards for supporting actor at the Golden Globes, British Academy Film Awards (BAFTA) and Screen Actors Guild (SAG) Awards.
Nominated twice in 2009 for Tropic Thuder (Supporting) and in 1993 for Chaplin (Leading), Downey finally took home his first Oscar at the 96th Academy Awards.
"Oppenheimer" received a total of 13 nominations including best picture. Co-star Cillian Murphy is up for Best Actor in a Leading Role for his performance as Robert J. Oppenheimer.
'Oppenheimer,' Lily Gladstone win big at 30th Screen Actors Guild Awards
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Downey has been open about his past struggles with drug addiction. He revealed in his 2022 documentary "Sr.," which pays tribute to his filmmaker father, that he was addicted to drugs by age 8.
A series of arrests for drug-related charges and a year in prison followed Downey's first Oscar nod 30 years ago, when he was 28.
The actor said recently that he's grateful he didn't end up winning in 1993.
"I was young and crazy," he said on "The View." "It would have put me under the impression that I was on the right track."
The Associated Press contributed to this report.