The Polish fourth seed went down 6-3 6-4 to China's Peng Shuai in their second-round clash at Flushing Meadows.
It continued Radwanska's poor record at the final grand slam of the year, having never advanced beyond the fourth round at the US Open.
Radwanska, who converted just one of seven break points, said Peng had simply produced in the big moments.
"I think every game was pretty tight and a lot of rallies," she said.
"Even the serve wasn't really the big in the weapon in that match, so every game could go either way.
"But I think in the important moments I think she was just playing a little bit better."
Radwanska described Peng, who hit 28 winners and 22 unforced errors, as "very consistent from both sides".
The 2012 Wimbledon runner-up has no idea why she struggles at the US Open.
"I really want to know the answer," Radwanska said.
"Then maybe I will find a way to play better here and just try another way to be in the second week.
"There is just something here that I can't really pass those rounds. Well, I have couple of years to try. Hopefully one day I will do it."