The unseeded Pennetta continued her unexpected run with a 6-4, 6-1 victory over No. 10 seed Roberta Vinci, earning a Grand Slam semifinal spot for the first time in her career.
Azarenka and Pennetta have split their two previous meetings, the last one having come in 2011, and if Azarenka gets to the championship match she will have done so without having to face anyone seeded higher than No. 13.
Azarenka made it to the finals of the U.S. Open a year ago, but was defeated on that occasion by Serena Williams.
Williams has appeared unstoppable once more during this year's tournament, steamrolling into the semifinals Wednesday with a 6-0, 6-0 crushing of Carla Suarez Navarro. Li Na will challenge Williams in the semifinals.
Williams has won eight tournaments this year and has captured 50 of her last 52 matches. One of her two losses in that stretch came against Azarenka in the finals at Cincinnati.