Shiffrin posted the fastest time in the opening run and went on to prevail by 33 hundredths of a second over Olympic champion Petra Vlhova of Slovakia with a total time of one minute 42.02 seconds at the lone women's World Cup stop on US soil.
Swiss Wendy Holdener finished third, 1.37 seconds behind home favourite Shiffrin, who has now won six of the seven World Cup slalom events held at Killington.
"It's a pretty incredible hill and especially in slalom I feel like I have a good mentality," Shiffrin said after her 55th World Cup slalom victory.
"And I feel like the crowd really, really helps me here... I say it every year, but it's so loud, and I can hear them cheering at every split where the intermediate times are.
"Every time I pass one, I hear them get louder, and I'm like, 'Oh man, I don't know if I'm ahead or behind, but either way, I've got a push'. So it's amazing to ski with that kind of energy."
Shiffrin, who placed fourth and first respectively in the World Cup slaloms in Levi earlier this month, was 0.19 seconds ahead of Germany's Lena Duerr after the first run at Killington.
Vlhova briefly took over after a remarkable second run but Shiffrin overtook her perennial rival with a blistering second descent of her own before pumping her fists to the delight of the home fans.
The win for Shiffrin, who finished third in Saturday's giant slalom, also gave the American her 141st World Cup podium, which trails only the 155 earned by Swedish great Ingemar Stenmark during the 1970s and 80s.
