The 36-year-old Williams, who is bidding for a record seventh title at Flushing Meadows as well her 24th major singles crown, started sluggishly in the night session at Arthur Ashe Stadium, allowing Pliskova to take a 3-1 lead in the opening set before rebounding to win 6-4, 6-3.
With a win she would break out of a tie with Chris Evert for most US Open titles, and equal Margaret Court's all-time record for Grand Slams. The 36-year-old American did not compete in NY a year ago, because she gave birth to her daughter during the tournament.
The last time No. 17 Williams and No. 8 Pliskova, another former world No. 1, met was in the semifinals of the 2016 US Open.
Pliskova got another chance when Williams batted a forehand into the net, but another booming serve, a backhand victor and an unreturnable serve saw her negotiate the danger. I think she's still the strongest.
Both players have reached Grand Slam semi-finals this year, del Potro at Roland Garros where he cruised past Isner in the fourth round and Isner at Wimbledon.
"When you don't play big points well, the match can get away from you", she said.
"She's been playing really well for actually a long time", Williams said of her semi-final opponent. It's a amusing phrase to say, but that's actually what happened - no one knew me the day before, and then the next day, it was like everyone knew me. "I was thinking, 'I can play better.' So that was the good news".
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Sevastova broke the 25-year-old American's serve twice in the opening set, then broke her again to take a 2-0 lead in the second.
Even Williams, from the moment she returned, has downplayed her expectations and assessed each win as little more than a surprise bonus step on a long road to returning to "Serena" form. Now, she has not only made it to her maiden grand slam quarterfinal, but she also became the first Latvian woman to make it to the US Open semifinal.
Soon after that, Williams went from trailing 4-2 to not only taking the first set but also leading 4-0 in the second. She's just going to ace you or play the best points on your chances.
"So the fact that I made it to the quarter-finals and played some really good matches and I just competed as hard as I could, I mean [there's] a lot to be proud of".
Stephens, who was visibly struggling under the sauna-like conditions, simply had no answer for the steady stream of drop shots sent her way by Sevastova, who later said she was not trying to take advantage of the sweltering conditions.
"It's been a few couple rough semis for me". After being down 3-1 and facing seven break points, Williams had won eight straight games.