Lewis fired a final-round three-under-par 69 to hold off defending champion Lexi Thompson, the 17-year-old closing with a round of 66.
“You have to hit it good here and hit some tricky putts,” Lewis said.
“It’s stressful this course. Somebody can get on a good run and make a lot of birdies. And 16, 17 and 18 are tough finishing holes.”
Lewis, whose only Major title came at the LPGA Kraft Nabisco last year, has now won three titles in Alabama in 2012 – the Mobile Bay LPGA Classic, the Shoprite LPGA Classic in June and now the Navistar LPGA Classic.
South Koreans Haeji Kang (68) and MJ Hur (68) shared third along with American Angela Stanford (70).
Overnight leader Lewis did not make the best of starts to the final round, bogeying the second hole before bouncing back with birdies on the fifth, ninth and 10th.
The American added another birdie at the 16th and sealed victory with pars on the final two holes.
“I knew making that putt was key,” Lewis said about the 16th hole. “It was downhill and it was so fast.”
Thompson, who began the tournament by matching the course record with a round of 63, started the day five shots off the pace.
But, after opening with a bogey at the first, she put the pressure on Lewis with birdies at the third, sixth and eighth holes before three birdies in a row from the 10th.
Thompson also birdied the 17th after deciding not to push for an eagle that could have forced a play-off with Lewis.
“I just figured lay-up and birdie with my wedge,” the 17-year-old said. “I’ve been more successful the last few years doing that.”
The LPGA now enjoys two weeks off before heading to Asia for the Sime Darby LPGA Malaysia.