The actor and singer – real name Nora Lum – took home the trophy for her role in Lulu Wang’s The Farewell.
Awkwafina was born in New York to a Chinese-American father and a mother who hailed from South Korea.
One of the star’s great-grandfathers was a Chinese immigrant in the 1940s.
Awkwafina’s other film roles include blockbusters Ocean’s 8 and Crazy Rich Asians.
Twitter was awash with praise for the actor and her historic achievement.
Earlier in the evening, Korean writer-director Bong Joon-ho won Best Foreign Language Film for Parasite, which will be released in the UK in February.
Last year, Sandra Oh became the first Asian star to win Best Actress in a TV Drama in over 40 years for her role in Killing Eve. The first was Yoko Shimada, an actor of Japanese descent who won in 1981 for Shōgun.
Earlier in the evening, Russell Crowe accepted his speech via a poignant letter he wrote while “protecting his family” from the bushfires back in his home country of Australia.
The ceremony’s top prizes went to First World War drama 1917 and Quentin Tarantino’s Once Upon a Time in Hollywood, which won Best Film in their respective Drama and Comedy categories.
Ricky Gervais hosted the ceremony and immediately shocked with a joke about Leonardo DiCaprio’s 22-year-old girlfriend, Camila Morrone, and Prince Andrew.
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