Lewis sank a 7-foot birdie putt on the 72nd hole to complete a 6-under 65 and capture the Walmart NW Arkansas Championship in Rogers, Ark. She finished at 12 under.
It was Lewis' third win in her last seven starts. Her next event is the Ricoh Women's British Open (July 10-13), where she is the defending champion.
"It's so hard to play here," said Lewis, the crowd favorite who went to the University of Arkansas. "I was more nervous than I was at the U.S. Open last week. It's just really special to win here."
Starting the day two shots behind 36-hole leader Wie in the 54-hole event, Lewis birdied three of her first six holes before bogeying No. 9. As several other players, including Lydia Ko, Cristie Kerr, Angela Stanford and Chella Choi joined the fray, Lewis put on a late charge, birdieing 15, 16 and 18.
Wie, whose week began with a whirlwind media tour of New York to celebrate her U.S. Women's Open win, never made any headway in her bid for a second straight win. She went 16 holes before making her first birdie. She shot 2-over 73 and finished four shots behind Lewis.
Wie was the only player among the top 14 finishers to shoot over par on Sunday. She parred her first eight holes, then bogeyed Nos. 9, 10 and 11 to fall off the pace.
Ko, Kerr and Stanford tied for second at 11 under. Ko, who birdied three of her last four holes, matched Lewis, Julieta Granada and Meena Lee for the day's lowest round, a 6-under 65. Kerr started fast with three birdies in a front-nine 33, but could manage just one birdie on the back. Stanford made six birdies and two bogeys in a 67.