Lewis entered the final round two strokes behind world No. 1 and defending champion Tseng, but the 26-year-old took the lead with a birdie on No. 9 and never looked back.
She went on to claim her first career LPGA victory, ending three strokes ahead of Tseng at 13-under 275 in wrapping up the tour's first major championship of 2011.
Lewis made several key putts down the stretch and logged a memorable save for par on No. 17, draining a 15-foot putt near the edge of the green while Tseng (2-over 74) stumbled to a bogey.
Katie Fulcher (69), Angela Stanford (73) and Morgan Pressel (76) were the distant third-place finishers six shots further back at minus-4.