The prize is the latest in what has been an excellent award season for the World War One drama, which also won big at the Golden Globes and the Producers Guild of America (PGA) Awards.
After winning, Mendes used his acceptance speech to share a story about his grandfather – who had been the inspiration for the film.
He told the crowd, “My grandfather inspired this film, and he made me, when I was 12, sign a contract promising I would write a novel by the age of 18.
“Obviously I’m not a freak so I didn’t do that, but I did do this. So I want to say thank you for him for that.”
It was the second time the director had won the DGA Award – but more than twenty years have passed since his last triumph for American Beauty in 2000.
This time round, his competition had come in the shape of Hollywood heavyweights Quentin Tarantino and Martin Scorsese, for Once Upon A Time… In Hollywood and The Irishman respectively, as well as Bong Joon-Ho for Parasite and Taika Waititi for JoJo Rabbit.
Meanwhile, Alma Har’el won the award for the First-Time Feature category for her film Honey Boy, which starred Shia LaBoeuf.
The DGA Award had come under fire after no women were nominated in the main category yet again – as has also been the case for the upcoming Academy Awards.