Kim Clijsters, whose Grand Slam title haul also includes last year's Australian Open, had not lost at the US Open since falling to compatriot Justine Henin in the 2003 final on the same Arthur Ashe Stadium court.
That just made her shock downfall all the more poignant.
"This feels like the perfect place to retire. I just wish it wasn't today," Clijsters said. "I gave it all and just wasn't good enough at the end of the match."
Robson snapped the Belgian's 22-match US Open win streak, smacking a tricky forehand winner on the line on the penultimate point and firing a service winner to claim the victory on her third match-point chance.
"I was just trying to play as hard as I could because I knew if I didn't Kim would dominate because she's such an aggressive player," Robson said. "I just went out there to keep getting the ball back and work my butt off."
On a day when Wimbledon and Olympic winner Serena Williams turned her left ankle in a doubles match and Britain's third-seeded Andy Murray became the first man to reach the third round, nothing topped Clijsters saying goodbye.
Clijsters, 29, made her final bow on the same court where she won her first Grand Slam title in 2005 and followed it up with crowns in 2009 and 2010. She had said she was leaving the sport for more time as a wife and mother.
"One of my biggest dreams came true in 2005 winning here," Clijsters said. "Every time I came back I was so inspired by the enegry that was out on this court and I played some of my best matches on this court.
"It has all been worth it. But I look forward to having the next part of my life coming up."
Robson, who was age five when Clijsters first played here, will next face Chinese ninth seed Li Na, who dispatched Australia's Casey Dellacqua 6-4, 6-4, in 87 minutes.
"Thanks to Kim for being such a great role model to me for so many years," Robson said.
Williams played with a bandage after being hurt in her doubles victory with sister Venus but did not speak to reporters after the match, so her fitness for a second-round match Thursday against Spain's Maria Jose Martinez Sanchez is unknown.
Murray's form looked just fine, however, as he fired 10 aces in a 6-2, 6-1, 6-3 romp over Croatian Ivan Dodig.
"I thought I played well," Murray said. "He was moving incredibly fast. You always have to play an extra shot against him. I moved my feet well."
World No. 1 Victoria Azarenka, this year's Australian Open champion, reached the third round while defending champion Samantha Stosur and third seed Maria Sharapova, the reigning French Open champion, advanced with ease as well.
Spanish fourth seed David Ferrer, Argentine seventh seed Juan Martin Del Potro and US ninth seed John Isner won their openers on the Flushing Meadows hardcourts.
The US Open saw nine men's comeback triumphs from two sets down in the first round, matching the record from 1989, including Serbian ninth seed Janko Tipsarevic's 4-6, 3-6, 6-2, 6-3, 6-2 victory over Frenchman Guillaume Rufin.
And Australian Lleyton Hewitt, the 2001 US Open champion, reached the second round by dispatching Germany's Tobias Kamke 4-6, 6-2, 6-1, 6-4.
Reigning Australian Open champion Azarenka reached the third round by defeating Belgian qualifier Kirsten Flipkens 6-2, 6-2 in only 65 minutes for her 50th match victory of the year.
"I'm proud of everything I have achieved this season," she said. "It has been a great year."
Azarenka, who has reached the last eight in every Grand Slam event except the US Open, will next face Chinese 28th seed Zheng Jie.
Australian seventh seed Stosur took an hour to beat Romanian qualifier Edina Gallovits-Hall 6-3, 6-0 to reach a third-round date with US 31st seed Varvara Lepchenko.
Russian third seed Sharapova ripped Spain's Lourdes Dominguez Lino 6-0, 6-1 to book a third-round match against 21-year-old US wildcard Mallory Burdette, ranked 252nd, who advanced with a 6-2, 6-4 victory over Czech Lucie Hradecka.
Ferrer, whose best Grand Slam showing was a 2007 US Open semi-final run, beat South African Kevin Anderson 6-4, 6-2, 7-6 (7/3) to reach a second-round match against Dutch qualifier Igor Sijsling.
Isner, the top American hope to end a nine-year US men's Grand Slam title drought, struggled to subdue Xavier Malisse 6-3, 7-6 (7/5), 5-7, 7-6 (11/9).
Del Potro, the 2009 US Open winner, advanced over France's Florent Serra 6-4, 7-6 (7/4), 6-4.