For six-times champion Williams, who is seeking her first Grand Slam title since becoming a mother last September, this may be her toughest test yet in New York as the Czech eighth seed has rediscovered the form that took her to the 2016 final.
Williams, who is three wins away from securing a record- equalling 24th Grand Slam title, survived a scare in her previous match when she needed three sets to dispatch Kaia Kanepi.
Pliskova has won all her matches here in straight sets, including a round of 16 clash with Ashleigh Barty in which she won all 10 of her service games en route to her third consecutive U.S. Open quarter-final.
Pliskova and Williams, who will kick off the evening session, have split their two career meetings, with the Czech having won their most recent battle in the 2016 U.S. Open semi-finals.
Stephens will kick off the day's action on centre court when she meets 19th-seeded Latvian Anastasija Sevastova for a spot in the semi-finals against either Williams or Pliskova.
World number three Stephens has settled nicely into her role as defending champion, approaching each match with a new swagger and with plenty of support from the home crowd.
Stephens had a straight sets win over Sevastova last month in a U.S. Open tune-up at Montreal on her way to the final.
Argentine Juan Martin del Potro, the 2009 champion, will cap the day session when he faces John Isner in a battle of towering big-servers.
Del Potro, seeded third, has won 81 percent of his first serves en route to the last eight while 11th-seeded Isner has won a staggering 85 percent of his own.
Holder Nadal will meet Dominic Thiem for the first time since he beat the Austrian in this year's French Open final.
The re-match caps the evening session and determines who faces the winner of the Del Potro-Isner clash.
(Reporting by Frank Pingue; Editing by Ian Ransom)
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