Lewis shot 3-under 69 to finish at 13-under 275, rallying from an early two-stroke deficit while going head-to-head with the world's top-ranked player.
She punctuated a tenacious back nine in gusty wind at Mission Hills with an improbable 20-foot par putt from the fringe on the 17th hole, prompting a celebration in the raucous gallery.
Tseng shot 74 with four bogeys, losing focus in her quest for her fifth worldwide title already this year. Lewis bogeyed the 15th hole to allow Tseng to pull within one stroke, but Tseng bogeyed the next two holes.
"I can't even believe it," said Lewis, who overcame scoliosis to become an elite golfer. "I've felt like I'm going to throw up all day. It's awesome. ... I just couldn't believe I made it (on the 17th hole). I thought I had a good shot from there, but I just tried to stay calm."
Morgan Pressel, Katie Futcher and Angela Stanford finished nine strokes behind Lewis in a third-place tie. Michelle Wie (75) and 2007 Kraft Nabisco champion Pressel (76) both faltered badly in their final rounds after starting the day within striking distance of Tseng and Lewis, with Wie falling into sixth place -- still the former child prodigy's best finish in a major since 2006.
Lewis led going into the final round of the 2008 U.S. Women's Open, finishing third in her first pro tournament. She established herself as a solid pro in the 21/2 years since, but still hadn't won.
CHAMPIONS TOUR: In Saucier, Miss., Tom Lehman pulled away for his second Champions Tour victory of the season with a final-round 69 at the Mississippi Gulf Resort Classic at Fallen Oak.
Lehman, who won the Allianz Championship in February, started the day with a one-stroke lead over Jeff Sluman and bogeyed the first hole to briefly fall into a tie.
He didn't make many more mistakes, with five birdies despite windy conditions that made for a more difficult challenge than Saturday, when Lehman shot a course-record 64. He finished the tournament at 16 under.
Sluman, Nick Price and David Frost tied for second, four shots back. Hale Irwin finished tied for seventh, earning his 200th top-10 finish on the Champions Tour.
EUROPEAN TOUR: In Agadir, Morocco, David Horsey had a birdie on the second extra hole of a three-way playoff to earn his second European Tour title, taking the Trophee Hassan II after a final round that included a hole-in-one.
Horsey was one shot ahead of defending champion Rhys Davies and Jaco Van Zyl at the par-4 18th, but stumbled to a double bogey that left him at 13-under 274.
Davies (69) missed a 4-footer for par that would have given him the win and Van Zyl (68) made par on the last to join the playoff.
All three parred the first playoff hole before Horsey won it on the second.
Horsey had his hole-in-one at the par-3 second, giving him the lead after being tied with Davies overnight.
Horsey became the fourth Englishman to win the event, after Peter Townsend (1978), Martin Gates (1994) and Roger Chapman (2000).
Thomas Bjorn set a course-record 62 to finish at 6 under in 15th place.