"It's a big confidence booster going into the last major of the year," said Thompson, who is projected to improve to second in world rankings. "I knew my game was in a good spot. I really committed to my shots this week and had some fun."
Ko shot a 72 to finish outright second, one stroke ahead of Australia's Minjee Lee, the New Zealander's challenge fading with a double-bogey at the par four 11th.
Holding a four-stroke lead, Thompson's drive found water at the 16th but the bogey did nothing to stop the 22-year-old from South Florida as she birdied the par-four 18th to capture her ninth LPGA victory.
She opened the three-day tournament with an eye-catching 63 and followed that up with a 66 for her second win of the year.
In keeping with the theme of the Indy 500, Thompson took a pair of victory laps around the famed oval next to the course, joining Indianapolis Motor Speedway president Doug Boles in a pace car.
"I'm all about driving fast," said Thompson. "I got it up to 122 (mph)."
Ko had her first top-10 finish since mid-June but struggled on the greens on Saturday.
“I just wasn't putting as well as I did the last few days and that makes a huge difference,” she said.
“When you're in the final round, final group, you kind of want those putts to drop and unfortunately that wasn't happening for me.”
Rookie Olafia Kristinsdottir, Iceland's first LPGA Tour player, finished fourth, chipping in for eagle at the 18th in her final round of 68.
(Reporting by Gene Cherry in Raleigh, North Carolina; Editing by Ian Ransom)
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