Webb set a record for most money won in a single LPGA Skins Game, collecting all but $50,000 of her total on the back nine. She took control on No. 12 by holing an 18-foot birdie putt to claim four skins and $120,000.
Webb holed another 18-foot birdie putt on No. 16 that was worth four more skins and $160,000.
"I could have played that well and come away with nothing," said Webb, who moved from ninth to second on the career LPGA Skins Game money list with $710,000. "That's the way the Skins Game works. I was putting aggressively on the back."
Sunday marked the return of the LPGA Skins Game following a four-year hiatus. England's Laura Davies, the all-time leader with $890,000 and winner of the last event in 1998, was shut out.
"I had my chances early on and didn't make my putts," Davies said. "Give Karrie credit, she played fantastic. The Skins is all about doing it at the right time and I didn't do it."
Sweden's Annika Sorenstam, who won 11 LPGA Tour titles last year, finished second with three skins and $70,000. Laura Diaz also claimed three skins and finished third with $60,000 in the four-player event.
"I made eight birdies, so that's great," said Sorenstam, the most dominant player on tour who has raised the possibility of playing in a PGA event this year. "Karrie made them when they counted."
Sorenstam took the lead after holing a six-foot birdie putt on No. 8 for $30,000 and her third skin, but there were no skins over the next three holes.
Diaz and Davies were eliminated after Sorenstam and Webb birdied the 16th hole. Webb earned her final two skins with a three-putt birdie putt on No. 17.
"This is a nice way to start the year," Webb said. "It certainly exceeded my expectations. I never expected to win that much money."