Keys, a US Open finalist in 2017, produced a disciplined performance to clinch a 6-1, 6-4 victory in 1hr 26min on the Arthur Ashe Stadium.
The American 17th seed will play second seed Aryna Sabalenka of Belarus on Thursday for a place in the final.
Czech ninth seed Vondrousova, who made history in July after becoming the first unseeded woman to win Wimbledon, was left ruing an inability to convert any of nine break points against Keys.
Keys by contrast seized every opportunity that came her way, converting all three break points she earned to advance to the last four of a Grand Slam for the sixth time.
Keys said the home support had helped her survive Vondrousova's nine break points.
"I love playing here, in front of a home crowd – you never feel like you can't get out of any situation," Keys said.
The American said she had decided beforehand to go on the front foot against Vondrousova.
"Just being able to stay aggressive and staying on the front foot the whole time," Keys said, who was beaten by semifinal opponent Sabalenka in straight sets when the two met in the quarterfinals at Wimbledon in July.
"It's going to be a lot of hard-hitting, not a lot of long points," Keys said of Thursday's semifinal.
"I'm just going to buckle up and get as many balls back as I can."
Vondrousova meanwhile admitted she had struggled to cope with the power of Keys' groundstrokes and serve.
"I felt like I was under so much pressure from the first point," Vondrousova said. "There wasn't so much to do, honestly. It was very tough.
"I was just trying to fight, run for every ball. She was just too good."
Keys got off to a blistering start, breaking Vondrousova's serve twice in the first set to open up a 4-0 lead.
The American then saved three break points in the fifth game before holding for 5-0. Vondrousova finally held to make it 5-1 in the next game, before Keys wrapped up the set.
Vondrousova found more consistency in her serve in the second set but once again her failure to capitalise on break point opportunities checked her momentum.
She spurned five break points for a 5-3 lead that would have left her serving for the second set, but was unable to take any of them as Keys got off the hook to level at 4-4.
In the next game Vondrousova found herself break point down after hitting a backhand into the net to give Keys a 30-40 lead.
The Czech then sent a forehand return into the net to leave Keys 5-4 up and serving for the match, and the American made no mistake, converting her third match point when Vondrousova sent a backhand return long.
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