The American ended a drought stretching back to his win at the British Open last year, which came two months after he claimed his first major at the PGA Championship.
Schauffele, who won Olympic gold in Tokyo in 2021, finished on 19-under par after a seven-under final round of 64 containing eight birdies and one bogey at Yokohama Country Club.
He calmly rolled in a short putt to close out the win, then took his cap off to acknowledge the crowd and embraced his caddie.
"It feels good, it's nice to know I've still got it," said Schauffele, who struggled with injury earlier in the year.
"It was a rough year, but my team dragged me through it."
Schauffele, who was part of the losing US Ryder Cup team two weeks ago, began the final round tied for the lead with Greyserman.
The pair were quickly joined by Michael Thorbjornsen after the 24-year-old American hit an eagle on the fourth hole.
Schauffele took the sole lead after the 14th hole and he never looked back, moving two shots ahead with a nerveless birdie on the 17th.
Greyserman made a last-gasp bid to make up lost ground, but his eagle attempt on the final hole pulled up agonisingly short.
Schauffele said it was "special" to get his 10th PGA Tour win in Japan, where his mother grew up and his grandparents still live.
"Hopefully I'm catching my stride," he said.
"It was a big learning experience with the injury this year."
Greyserman was looking for his first PGA Tour title after finishing as runner-up four times, including at last year's tournament in Japan.
Thorbjornsen finished third, three strokes behind Schauffele.
Schauffele's Ryder Cup team-mate Collin Morikawa finished tied for 14th on 10-under par.
Japan's Hideki Matsuyama was in a share of 20th place on eight under.
American Matt McCarty shot the round of the day, rattling in an incredible 12 birdies to card a 60.
McCarty, who birdied eight straight holes on the back nine, bogeyed the 18th to deny him the rare feat of a sub-60 round.
The Baycurrent Classic is the only US PGA Tour event currently staged in Asia.
It was previously known as the Zozo Championship and first held in 2019 when Tiger Woods was the inaugural champion. Matsuyama won it in 2021.