Against No. 6-seeded Angelique Kerber, Williams -- suffering from a chronic autoimmune condition, Sjogren's Syndrome, which saps her strength -- looked every one of her 32 years. She lost to the powerful German 6-2, 5-6, 7-5 in a second-round match.
The contest ran 2 hours, 45 minutes long.
Kerber, a semifinalist here a year ago, has now beaten Williams three times this year, including their third-round encounter at the Olympics in London.
Slowly, as the match progressed, Venus found her form and the crowd at Arthur Ashe warmed up, too. The Williams sisters have never been well supported here at the National. Thursday felt different.
"Today I felt American for the first time at the U.S. Open," Venus said. "So I've waited my whole career to have this moment, and here it is."
Truth is, she just ran out of steam.
"I was fighting her today and, unfortunately, myself," Venus said afterward. "I couldn't put more than two points together without making a few errors. I didn't help myself out today."
A sign of the troubling times: This is the first time in 16 years that Venus didn't reach at least the third round of a Grand Slam singles match in a calendar year.
"Yeah, I mean it's unbelievable," Kerber said afterward. "Today it was so tough, the match. Venus is such a great player. She has won many Grand Slams.
"Everybody was against me. I just tried to focus on me, fighting every point until the last."
There was a time when Venus, not sister Serena, had the best serve in tennis. Three years ago in Paris, she struck one 129 mph -- the second-fastest in WTA history.
But Thursday night her once-formidable serve was ordinary -- on the occasions it actually found the service box.
During the match, her hitting partner, David Witt, seemed resigned.
"The serve is the key to her entire game," he said during the first set. "It's going to be hard to win if she can't get first serves in."
Kerber, impossibly, broke Williams' serve five straight times at one point.
For the match, Venus' first-serve percentage was an anemic 54 percent and she won only 19 of 54 second-serve points. The rest of her game was lethally loose, too. Williams had only one ace, 16 double faults and 60 unforced errors. This is what happens when you can't practice properly; timing, in tennis, is everything. Venus, who used to be dangerously dialed in, had difficulty stringing even two or three points together.
It might have seemed unfair that a two-time U.S. Open champion was forced to play the No. 6 seed in the second round, but this is where she is these days. Her ranking of No. 46 isn't high enough to protect her in the early rounds.
Recent results had raised hopes that Venus might make a decent showing here. She made the semifinals at Cincinnati, defeating the No. 3 seed Sam Stosur and No. 7 Sara Errani along the way.
After the first set, Venus settled down and her groundstrokes started dropping in. She broke Kerber's serve to level the second set at 2-all. She started coming to the net more aggressively and forcing Kerber's hand, bringing the score to 3-all. And then 4-all and 5-all.
When Venus busted out her first ace of the night -- in the 19th game -- it seemed like a sign. She broke Kerber (for the sixth time) and extended the match.
Both women have been exceptional in three-set matches this year; Kerber was 18-2 while Venus was 8-2.
It took a while, but late in the second set, Venus seemed to be remember that her best chance to win involved rushing the net whenever possible.
As Venus climbed back into the match, the crowd on Arthur Ashe started to get into the match. At times, they cheered service misses by Kerber and yelled out while she was hitting groundstrokes. Kerber, slowly, lost her composure. She took to hiding under a towel on the changeovers.
Serving at 5-all, two wobbly Venus errors gave Kerber her ninth service break.
Kerber, serving for the match for the second time, converted. In the end, the favorite won. Casual tennis fans might not know it, but Kerber's 55 match wins lead all WTA players this season.
Venus, meanwhile, has accumulated the most victories of anyone in the women's draw (61) at the U.S. Open, in 14 tournaments, another reminder of her sustained excellence.
Those are the kind of numbers that make it feel like the end of an era.
With Roddick and Kim Clijsters departing, Venus and Serena -- with their 21 combined majors -- represent the last of their generation of champions. Serena, who turns 31 next month, is the favorite to win this tournament.
To this point, Venus has given no indication that she is considering retirement. From everything she has said, she'll be back for 2013.
"When you're ready, you're ready," Venus said of Roddick. "If I was out there and people were killing me, maybe time to hang it up. But I just have to find the answer within myself. I'm playing my game and eventually [the shots] will land."
Everybody, including Venus herself, is just going to have to recalibrate their expectations.