Writer-director Jordan Peele picked up the trophy for best original screenplay for Get Out, a dark satire of the African-American experience and liberal white guilt.
"This was a passion project. It was something I put my love into, I put my soul into, so getting this from you means so much," Peele said as he picked up his trophy.
"I started writing it in 2008 and there were a lot of ups and downs." The film, starring Daniel Kaluuya, has already landed Peele best first time feature at the Directors Guild of America Awards and is nominated for four statuettes at the Oscars, to be held on March 4.
Get Out beat out The Big Sick, I, Tonya, Lady Bird and The Shape of Water. The evening was hosted for the third year in a row by Emmy and Grammy-winning actor, writer and comedian Patton Oswalt, who began by light-heartedly chastising the WGA for bringing him back.
"Given the current atmosphere, maybe get a female host next year. There are hilarious comedians and writers out there," he said.
James Ivory scooped the prize for best adapted screenplay for his work transforming Andre Aciman's 2007 novel Call Me by Your Name into the film of the same name, starring Timothee Chalamet.
Luca Guadagnino's paean to the universal heartbreak of first love, set in 1980s northern Italy, bested highly-touted rivals, including The Disaster Artist, Logan, Molly's Game and Mudbound. It is also nominated for four Oscars, including nods for Ivory's screenplay, best picture, best actor for Chalamet and best original song.
Best documentary screenplay went to Brett Morgen for Jane, a study of the life and work of celebrated primatologist Jane Goodall, whose groundbreaking chimpanzee research revolutionised people's understanding of the natural world.
In the television category, Hulu's The Handmaid's Tale won both best drama and best new series, while HBO's Veep took best comedy series.
The WGAs is one of Hollywood's last major prizegiving ceremonies ahead of the Academy Awards.
It is not considered as reliable a predictor of Oscars glory as the other guilds' prizegiving nights, however, as members can only shortlist scripts written under WGA guidelines or those of several international partners.