The unseeded Pennetta is now through to the first Grand Slam semi-final of her career after the 31-year-old beat fellow Italian Roberta Vinci in Wednesday's quarter-final, 6-4, 6-1.
The world No. 83 Pennetta needed just over an hour to beat the 10th-seeded Vinci after playing an efficient game with 23 winners and converting six of 12 break points to win through to the semi finals.
The run at this year's Flushing Meadows completes a remarkable comeback for Pennetta after her 2012 was ravaged by injury ending with wrist surgery as she ended the year outside of the top 40 for the first time in nine years.
Before this year's US Open, Pennetta had reached three previous US Open quarter finals but this is her first time into the semis. Remarkably, the Italian has never advanced past the fourth round of any other Grand Slam tournament.
The US Open has always been where she has felt most at home and now she is only two wins away from what would be a remarkable tournament victory, however, standing in her way still are the world's top two players.
At 30 years of age and after several years struggling, unseeded Slovak Daniela Hantuchova had also made a terrific run to the quarter finals, but that came to an end on Wednesday when the world No. 2 Azarenka proved too good winning 6-2, 6-3.
Hantuchova's serve simply couldn’t hold up against Azarenka and the Belarusian broke the serve of the Slovak seven times on the way to the straight-sets win in one hour and 16 minutes.
After Serena Williams and Li Na set up the first semi-final with their quarter-final victories on Tuesday, the second is now set at the US Open between Pennetta and Azarenka.
The pair have only ever played one another twice on the WTA Tour previously and never before at a Grand Slam. Azarenka won the first meeting 6-1, 6-4 in Stuttgart and then Pennetta prevailed 6-3, 6-7 (7), 6-4 in Dubai in 2011.