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Halep raced into a 5-0 lead in the opening set, breaking the defending champion three times and also saved three break points at 0-40 down in the fourth game.
Novak Djokovic was made to work hard by Casper Ruud in blustery conditions.
Defending champion Nadal was stunned by Argentine Diego Schwartzman in the quarterfinals.
Pliskova's exit marked the worst performance by a women's top seed in New York since Simona Halep's opening round defeat in 2018.
Romanian Halep joined world No. 1 Ash Barty, defending champion Bianca Andreescu, Elina Svitolina, Kiki Bertens and Belinda Bencic in skipping the event at Flushing Meadows due to COVID-19 concerns.
Meanwhile, world No. 1 Novak Djokovic headlines the initial men's singles entry list for the US Open, the organisers have announced.
The United States Tennis Association received the green light to hold their marquee tournament in New York as scheduled from August 31 to September 13 without fans.
Novak Djokovic, Ash Barty and Simona Halep have all indicated they would have concerns about playing the tournament under the health protocols designed to keep them safe.
Halep, 28, is currently back in her native Romania where she has been locked down at home for 22 days, only popping out briefly to jog around the grounds of her residence.
Tennis players around the world have hit out at the lack of communication from the game's governing bodies in the wake of the French Open being moved to September from May because of the coronavirus pandemic.