The 39th-ranked Peng won 6-3, 6-4 in the second round Wednesday, giving China a big win in the tournament with third-ranked Li Na out with a knee injury.
The U.S. Open is the only Grand Slam tournament in which Radwanska, the 2012 Wimbledon runner-up, has failed to reach the quarterfinals.
Peng had been 3-22 against top-five opponents, the last victory coming in 2011. That year was also the last time the 28-year-old made the third round at the U.S. Open.
On Wednesday, she won a 27-point rally with a sizzling backhand winner down the line to set up her third match point, then clinched victory with another backhand winner deep into the corner.
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