Three strokes ahead of playing partner Ryu entering the round, 20-year-old Wannasaen closed with a four-under 67 to finish at 20-under 264 at Highland Meadows in Ohio.
Ryu shot 65, also birdieing the final two holes.
"Last day, I cannot like calm down because my heart is like boom, boom, boom, boom," Wannasaen said. "Every hole."
Wannasaen won the Portland Classic last year.
"Right now, I'm feel like I'm going looking for third trophy," Wannasaen said. "Yeah, I think it's coming."
"She made me a little bit nervous," Wannasaen said.
Ryu had six birdies and a bogey on the back nine.
Defending champion Linn Grant of Sweden and Ssu-Chia Cheng of Taiwan tied for third at 14 under, each shooting 68.
"Going home for two weeks now," Grant said. "Just kind of relax a little bit before the Olympics."
China's Xiyu "Janet" Lin (70) and Mary Liu (69) were 12 under. Lin was the highest-ranked player in the field at No.15 in the world.
Australian Sarah Kemp had her best result of the year when tied for seventh after a closing 70 left her 10 shots behind the winner, while countywoman Grace Kim improved with a 67 to be tied 33rd at five under.
Stacy Lewis, the 39-year-old Texan who was born in nearby Toledo, shot 70 to tie with Kemp and four others for seventh at 10 under. She won the last of her 13 LPGA Tour titles in 2020.
"I'm exhausted, but it was a great week," Lewis said. "It's some of best golf I've played all year. Played good today. Just couldn't get anything close to the hole."
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