World number ones Sinner and Swiatek target US Open quarter-finals
Top seed Sinner, who won his maiden Slam at the Australian Open this year, takes on Tommy Paul while 2021 New York champion Medvedev meets Portuguese outsider Nuno Borges.
French Open champion and women's world number one Iga Swiatek, meanwhile, hopes to take another step closer to a second US Open title when the 2022 winner faces Liudmila Samsonova of Russia.
Sinner, 23, faces Paul of the United States hoping to become the only man this year to reach the quarter-finals at all four Grand Slams.
The Italian made the last-eight in 2022 where he squandered a match point in losing to eventual champion Alcaraz.
His Spanish rival has been removed from the New York equation this time around after the world number three and reigning French Open and Wimbledon champion was knocked out in the second round.
Paul, the 14th seed, is looking to join compatriots Frances Tiafoe and Taylor Fritz in the quarter-finals as the US looks for a first male Grand Slam champion since Andy Roddick triumphed in New York in 2003.
"I don't know if I'm thinking, like, 'opportunity' too much," Paul said.
"But it's definitely an opportunity to play on Arthur Ashe Stadium so I'm looking forward to that."
With four-time champion Djokovic and Alcaraz both eliminated, fifth-seeded Medvedev is the only former champion remaining in the draw.
The Russian faces 34th-ranked Borges in a rematch of their Australian Open last-16 clash this season.
Medvedev aims to reach the quarter-finals in New York for the fifth time in the last six years.
All-Aussie clash
If Sinner and Medvedev come through their assignments, they will meet in the quarter-finals in what would be their fourth clash of 2024.
Sinner came back from two sets to love down to defeat the mercurial Medvedev in the Australian Open final and came out on top in the Miami semi-finals.
Medvedev avenged those losses at Wimbledon in a five-set quarter-final victory.
The 27-year-old Borges is looking to defeat a top 10 player for the first time and become the first Portuguese man to reach a Grand Slam quarter-final in the Open era.
Swiatek will play her 100th Grand Slam match when she meets 16th seed Samsonova who is chasing a first ever last-eight spot at the Slams.
Poland's Swiatek holds a 3-0 head-to-head edge over Samsonova but the 25-year-old Russian will be buoyed by making the quarter-finals of both WTA 1000 events in Toronto and Cincinnati on the eve of the US Open.
Elsewhere in the women's draw, Russia's Diana Shnaider can reach her first Slam semi-final when she takes on US sixth seed Jessica Pegula.
Caroline Wozniacki, the runner-up to Serena Williams in 2014, faces Brazil's Beatriz Haddad Maia.
The winner of that clash will take on 2023 semi-finalist Karolina Muchova who knocked out French Open and Wimbledon runner-up Jasmine Paolini, the fifth seed, 6-3, 6-3.
Muchova, ranked at 52, who only returned to the tour in June after 10 months out with a wrist injury, has yet to drop a set at the tournament and knocked out two-time champion Naomi Osaka in the second round.
The men's last-16 line-up on Monday is completed by Britain's Jack Draper facing unseeded Tomas Machac of the Czech Republic while Alex de Minaur and Jordan Thompson clash in an all-Australian duel.
