Known as the "Tiger" for her ferocious determination, the 35-year-old had looked doubtful for the Games after a crash last April but fought back to fitness and produced one of her greatest runs on a foggy Olimpia delle Tofane piste.
France's Romane Miradoli took silver, 0.41 of a second slower, with Austria's Cornelia Huetter third, according to provisional results.
Sixth out of the start hut, Brignone threw caution to the wind on a challenging course that perfectly suited her technical skills. It proved too tough, however, for some of her rivals, including American downhill champion Breezy Johnson, who walked away from a high-speed crash into the netting.
Giant slalom world champion Brignone was accompanied by huge roars from the packed grandstand as she blasted across the finish line in 1:23.41 before taking her place in the leaders' seat and waiting.
10 of the first 24 starters failed to finish, including Brignone's teammate Sofia Goggia, although for a while it looked as though Huetter and then Miradoli might rip up the script.
Brignone puffed out her cheeks as they narrowly failed to beat her time, and after that, no one came close.
"I was expecting my skiing to be really confident and try to make every turn clean and be, not perfect, but to let my skis go and be smooth through the terrain," Brignone said.
"I tried to always be in front of the slope and to attack. I didn't expect anything else."
Asked if she thought she could take gold so soon after returning to competitive action, she said: "No, never. That's maybe why I did it, because today I was an underdog. I was an outsider, but I know what I can do with my skis.
"It's crazy. I don't think I've realised it."
Overall World Cup champion Brignone faced a race against the clock to make her home Olympics after the crash at the national championships left her with multiple leg fractures and a torn ACL. She only returned to the World Cup in late January and made the start list for the downhill, finishing 10th.
Her gold medal was the first by an Italian Alpine skier at the Milano-Cortina Games and completes her set after a silver at the Beijing Games in 2022 and bronze at PyeongChang in 2018 - both in giant slalom.