Keys, runner-up in 2017, has suffered a handful of early exits at her home Grand Slam in recent years but has excelled in the 2023 edition and is flourishing under the bright lights at Flushing Meadows.
She next faces second seed Aryna Sabalenka, who dispatched China's Zheng Qinwen 6-1 6-4 earlier on Wednesday to reach her fifth Grand Slam semi-final in a row.
"I just love it here. I love playing here. In front of a home crowd you can never feel like you can't get out of any situation," said Keys, who fended off all nine break points she faced during the match.
"I knew I was going to have to keep trying to get to the net, be aggressive."
The match got off to an unusual start as the chair umpire was forced to stop play midway through the first game for several minutes when a spectator needed medical attention.
Keys was not rattled by the incident and began her demolition once play resumed, breaking Czech Vondrousova to love in the second game and converting on another break point chance with a fine forehand winner in the fourth.
Ninth seed Vondrousova had withdrawn from her doubles campaign after a three-setter against Peyton Stearns in the fourth round left her with a sore arm and she looked like she lacked firepower against Keys.
And while she stepped up a gear in the second set, improving her serve considerably, she was still unable to seize the momentum, failing to convert on five break points in the eighth game alone.
Keys broke her opponent in the ninth game and let out a cheer as she forced Vondrousova into a backhand error on match point.
Vondrousova, who served up five double faults in the match, made no excuses for her defeat and told reporters that Keys was simply too good.
"I don't think it was nerves. I played, you know, some good points. It wasn't enough," she added.
"I think from her side it was so good on the serve. Yeah, was just trying to find a way. Just all credits to her today."
Keys expects a tough challenge from Sabalenka, who beat her in the Wimbledon quarter-finals and is assured of the world number one spot when the rankings are updated after the tournament.
"Almost a completely different match tomorrow," she said. "It's going to be a lot of hard-hitting, not a lot of long points."
Keys spoke last year about a "dark pit of despair" she found herself in after her career stalled due to the pressure of trying to stay in the upper echelons of the sport, but she feels that playing in the majors usually has a positive impact on her performance.
"I think I just find another gear when it comes to Slams," Keys told reporters. "Part of it is that I put a little bit more pressure on myself, which is a good thing and also a bad thing sometimes.
"But I've just peaked at the right time, I guess. I haven't had too many disappointing exits at Slams."
She says that putting the right type of pressure on herself is a delicate balancing act.
"Sometimes I do it well and sometimes I do it really badly, but I think it's reminding yourself, these are the matches that you grow up dreaming of. These are the moments you want to be in," said Keys, who booked a rematch with Sabalenka for a place in Saturday's final.
"So that kind of pressure of, it's the big stage, but also just the reminder of this is literally what we've dreamed of. These are the moments that you're practising for and you're playing for and you're constantly trying to get back to."
