Brignone, second in the super-G a week ago, led after the first run, and again put in the fastest time on her second to win by 0.90 of a second over New Zealand's Alice Robinson, who took silver and her first world championship medal.
America's Paula Moltzan battled to claim the bronze medal, overcoming Norway's Thea Louise Stjernesund by one-hundredth of a second.
Brignone had finished second behind Mikaela Shiffrin in this event in 2023, and took the silver medal at the 2022 Olympics. The Italian also has a giant slalom silver medal from her first world championships in 2011.
"Gold in the giant slalom is something I dreamed of throughout my career, I managed to stay calm after the first run, I knew I had a good lead," Brignone, who won a second world championship gold after her alpine combined victory in 2023, said.
Brignone, fourth out of the gates, set a blistering pace on the first run for the rest to follow, and Robinson was the only rival to get within one second of the Italian, 0.67 seconds behind.
Her dominance, especially in the second half of her run, left just six racers less than two seconds behind Brignone, including her expected rivals Moltzan, Lara Gut-Behrami and Sara Hector.
Before the big guns came out for the second run, Albania's Italian-born 18-year-old Lara Colturi was the surprise leader in her first world championships appearance but was finally overtaken by Stjernesund.
With the top five still to come, Stjernesund had a nervous wait to see if her time would earn a medal, and neither Hector nor Gut-Behrami could overtake the Norwegian.
Moltzan then took over at the top by the slimmest of margins, before Robinson set the fastest time of the second run to pile the pressure on Brignone.
Yet the Italian seems to get better with age, and in a superb season where she leads the overall World Cup standings, Brignone finished the job in style.
"At the World Championships we know it's all or nothing, I had the opportunity to go full throttle, today I was fine, I was focused on skiing," Brignone said.
"So much so that in the second run for a moment I was falling asleep and I said to myself 'move'. I'm out of breath but I was fine, I arrived at this event relaxed and at my best. I have to enjoy it as soon as it sinks in."
Reigning champion Shiffrin announced on Monday that she was not mentally ready for this race, having returned to racing in January two months after a crash during a giant slalom race left her with a puncture wound in her abdomen.
This was Italy's second gold medal of the championships after they won the mixed team parallel event on the opening day.