Pennetta completed a 6-2 7-6(3) win over Romania's Simona Halep but it was anything but a routine straight-sets victory.
After winning the opening set and building a 4-2 lead in the second, Pennetta suddenly lost her way as the hard-hitting Halep began to find her rhythm.
The Romanian, one of the hottest players on tour after capturing four WTA titles since June, reeled off the next three games in a row.
Then she reached set point on her own serve before play was suspended because of a thunderstorm.
The match did not resume for nearly five hours but when it did, the unseeded Pennetta burst out of the blocks quicker at Louis Armstrong Stadium.
The 31-year-old successfully saved the set point and broke Halep's serve to level the score at 5-5. And although she lost her own service game to fall behind again, she immediately broke Halep for a second time then won the tiebreaker.
"Today was a really tough match for me," said Pennetta. "It was tough to come back after so many hours.
"Waiting all day...then starting a game, it's not easy to focus."
Pennetta has never made it past the fourth round at any of the other grand slam but has flourished on the Flushing Meadows hardcourts, reaching the quarter-finals in the Big Apple in 2008, 2009, 2011 and now this year.
"New York is New York guys, " she said in a courtside interview. "I love it."
Pennetta faces a tough challenge because her next opponent, fellow Italian Roberta Vinci, is one of her closest friends.
"It's going to be really bad for both us, it's not easy to play with your friend," said Pennetta.
"It's strange because I grew up with Roberta and we've known each other since we were eight-years-old.
"We know each other really well...20 years or more, because we live almost in the same place, just 35, 45 kilometers."
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- Simona Halep