Novak Djokovic recovered from a set down to get past American qualifier Zachary Svajda, as Briton Emma Raducanu had a far easier time advancing into the US Open third round.
But Lulu Sun's tournament came to an end, the New Zealander beaten 6-2 6-3 by Elise Mertens, of Belgium, on Wednesday (local time).
It was the best result for Sun in a grand slam since the 23-year-old made the second round at Wimbledon last year.
She took three sets to beat Colombia's Camilla Osorio in the first round in New York.
Svajda, who poked fun at his own long odds against the former world No 1 in a now-viral TikTok video, put up a surprise early fight to the delight of the home fans but was let down by an apparent leg injury midway into the match.
Djokovic, of Serbia, next plays the winner of the match between Briton Cameron Norrie and Argentina's Francisco Comesana.
Carlos Alcaraz powered into the third round, with a dominant 6-1 6-0 6-3 win over Italy's Mattia Bellucci.
The Spaniard broke his opponent's serve seven times without facing a single break point in the first match of the evening session, sending down 32 winners and winning 86% of his first serve points. Next up for Alcaraz is Italian Luciano Darderi.
American fourth seed Jessica Pegula followed on Ashe with a routine 6-1 6-3 win over Anna Blinkova and will next play three-time finalist Victoria Azarenka.
The Belarusian Azarenka became only the fifth woman in the professional era to claim 100 or more singles main draw wins at the hardcourt majors as she beat Anastasia Pavlyuchenkova 6-3 6-3 earlier in the day at Stadium 17.
The 22-year-old had not won a US Open match since lifting the trophy in her remarkable run to the title in 2021 but appears in solid form this year, as she made just eight unforced errors.
"I'm particularly happy, because on the court, I felt like my opponent was playing really good tennis. I thought that she was very dangerous," she told reporters. "So I'm very pleased with how I kept dictating the points, I kept dictating the play."
Draper withdraws
Raducanu will face ninth seed Elena Rybakina of Kazakhstan in the third round. She continues in the tournament without British compatriot Jack Draper, who withdrew before his second round meeting with Zizou Bergs due to an arm injury on Wednesday.
American fourth seed Taylor Fritz got past South African Lloyd Harris 4-6 7-6(3) 6-2 6-4 in the second match of the day on Armstrong, with Swiss qualifier Jerome Kym waiting for him in the third round.
Fritz is among the top contenders hoping to break a 22-year American men's drought at the tournament, along with Frances Tiafoe, who beat qualifier Martin Damm 6-4 7-5 6-7(8) 7-5.
"You've got to be brave, you've got to be courageous - there's no free lunches out here," said Tiafoe, who hopes to go all the way after reaching the semi-final twice before.
American 10th seed Emma Navarro swatted aside her compatriot, wild card Caty McNally, 6-2 6-1, while the Norwegian 12th seed and former finalist Casper Ruud fell to Belgian Raphael Collignon 6-4 3-6 3-6 6-4 7-5.
Medvedev fined
Former champion Daniil Medvedev was fined a total of $US42,500 ($US72,500) for his spectacular meltdown during a loss to France's Benjamin Bonzi at the start of the week.
The Russia lost 6-3 7-5 6-7(5) 0-6 6-4 on Sunday but it was his behaviour in the third set that dominated the headlines, when the 2021 champion launched a tirade against the umpire and whipped up jeering fans who stopped his opponent from serving. He then smashed his racket.
While Medvedev collected $US110,000 for his first-round appearance, he coughed up fines of $US30,000 for unsportsmanlike conduct and $US12,500 for abusing his racket, the US Open said.
