Williams and Alcaraz rebounded from a slow start to defeat New Zealand's Erin Routliffe and Briton Lloyd Glasspool 5-3 4-1 in the first round on Tuesday (Wednesday AEST), but only after another superstar partnership between world No.1 Aryna Sabalenka and all-time great Novak Djokovic got knocked out.
Fans in the Arthur Ashe Stadium rose to salute Williams as she played her first match at the US Open match since 2022, when she was beaten in the singles by Australian Ajla Tomljanovic, while Alcaraz got back to action for the first time in any match since April 14.
With a white sleeve on his injured right arm, Alcaraz's timing, movements and serve looked off as fans chanted, "Let's go, Serena, let's go!" The decorated star of the show then delivered.
Williams, back at age 44, carried Alcaraz for much of the first set, winning 15 points to his nine to rally back and take the set.
"I'm playing with the one and only Serena Williams," Alcaraz said in a mid-match interview.
"Just enjoying. Trying to do the things she taught me to do."
Alcaraz eventually found his groove, before the pair cruised in the second, setting up a quarter-final against Belinda Bencic and Flavio Cobolli - which they subsequently lost 5-4 (7-4) 4-1.
"It's always such an amazing place to be here," Williams said.
"I never expected to be back on this court, so it was just a really cool moment. I never thought this would happen."
The winners advanced to the semi-finals on Wednesday (Thursday AEST), with the champions getting $US1 million ($A1.4 million) in the second year of the new mixed doubles format that's designed to attract top players.
Earlier, Sabalenka and Djokovic were beaten 1-4 4-2 (10-2) by doubles specialists Katerina Siniakova and Henry Patten, who brought the house down when the Czech star Siniakova ended the match by hitting an ace past the great Djokovic.
"Kat acing Novak on match point was pretty fun," Briton Patten laughed.
Married pair Elina Svitolina and Gael Monfils then edged Siniakova and Patten 5-4 (8-6) 4-5 (3-5) 10-8 in the quarters.
"Happy wife, happy life," Monfils, who'll turn 40 on September 1, beamed in their post-match interview after a kiss and hug on the court.
The tournament now has a scoring format that guarantees quick matches that shouldn't tax the players too much, with tiebreakers at 4-4 and a 10-point breaker instead of a third set.
