Switzerland's Wendy Holdener thrilled the home crowd with silver to add to her Alpine Combined gold she won last week, while Sweden's Frida Hansdotter took home the bronze.
Shiffrin's 1:03.16 was the best effort of the second run and temporarily put her in first place, but Worley's 1:03.54 proved enough to see her regain the gold she lost to Anna Veith two years ago.
That Shiffrin won on Saturday isn't a surprise.
Overall World Cup leader Shiffrin, the hot favourite in Sunday's slalom, was third after the first leg but leapfrogged Goggia into the silver medal position with a strong second run.
"One year ago it was much more hard, but I'm happy to say that I'm healthy again and can ski, and ski fast!"
Shiffrin also has 28 World Cup wins and three slalom discipline titles to her name.
"It's the first time I've made it to the finish in a giant slalom in St Moritz!" said Shiffrin.
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Winning the first run by 0.38 seconds over Holdener, Shiffrin crushed the second run, on a course set by her coach Mike Day, to extend her victory margin to 1.64 seconds.
She also became the first US woman to win two medals at a world championships since Lindsey Vonn in 2009. Lindsey Vonn sits behind her with the two she earned in the downhill and giant slalom in 2009.
"To be honest, I don't really know what that means yet", Shiffrin said (via the Denver Post). "But I felt really good about my second run". "I want to be the best skier, not just the fastest skier but the best technically".
She has won the slalom at every major event since she was 17 - world championships in 2013, 2015 and 2017, plus the Olympics in 2014. "I'm just going to try to ride this wave, get a little training tomorrow, and then go out and try to attack on Saturday".
Eagle-Vail's Mikaela Shiffrin announced herself as a force to be reckoned with in giant slalom on Thursday, claiming a silver medal in the event at the World Alpine Ski Championships in St. Moritz, Switzerland. When the World Cup resumes next weekend, she will have a huge lead in the overall standings, a pursuit that should end with her being crowned the youngest World Cup overall champion since 2003.
Worley admitted to further nerves over an error high up a Corviglia course basking in bright sunshine that saw snow rapidly melting on the second run.
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