"It's disappointing for me personally not for America as a whole," Isner said.
It was the third straight year that these two men faced each other in the third round in New York, and Kohlschreiber won them all. He eliminated the big-serving, 6-foot-10 Isner in five sets in 2012, and in four sets in 2013.
Isner only converted 1 of 12 break points he accumulated.
"Got a little tight, to be honest, and didn't move my feet on some points that I really needed," Isner said, resting his chin on his left fist. "I had chances. I just didn't convert."
The 29-year-old Isner is best known for winning the longest match in tennis history, an 11-plus-hour marathon spread over three days that ended 70-68 in the fifth set at Wimbledon in 2010.
Currently, he is the only U.S. man ranked inside the top 45, and has made clear he does not necessarily enjoy that distinction.
Fans at Louis Armstrong Stadium tried to boost their guy with chants of "Let's go, John!" And they roared throughout the fourth set, especially when Isner would edge ahead within a game.
But this one mainly came down to the tiebreakers, usually a strong suit for Isner: He entered the day 37-17 in those set-deciders this season, while Kohlschreiber was only 9-11.
"He was just better," Isner said. "I've got to be better. I know I can be. Just not showing it."Earlier Saturday, 57th-ranked Sam Querrey entering the day, the only other man from the host country remaining of the 12 originally in the draw put up little resistance while bowing out against No. 1 Novak Djokovic 6-3, 6-2, 6-2.
Kohlschreiber now will face seven-time major champion Djokovic in the fourth round.
Other fourth-round matchups: No. 3 Stan Wawrinka, the Australian Open champion, against No. 16 Tommy Robredo or 19-year-old Nick Kyrgios; 2012 U.S. Open champion Andy Murray against No. 9 Jo-Wilfried Tsonga; No. 5 Milos Raonic against No. 10 Kei Nishikori. Wawrinka advanced when Blaz Kavcic withdrew because of pain in his right foot.
Given Isner's history against Kohlschreiber at the U.S. Open, it's tough to call that result surprising, even if the American is ranked higher and is 4-0 against the German everywhere else they've played.
Instead, look to the women for the "Did that really happen?" results. In the latest of a series of stunners, fourth-seeded Petra Kvitova who won her second Wimbledon title last month was sent home with a 6-4, 6-4 defeat against Aleksandra Krunic, a 21-year-old qualifier from Serbia who is ranked 145th.
That means that the women seeded 2, 3 and 4 behind No. 1 Serena Williams are all gone before the end of Week 1.
"I'm an outsider," Krunic said. "I honestly didn't know what to expect from myself at all. You know, I don't know my limits."
Of the top eight women, only Williams, No. 5 Maria Sharapova and No. 7 Eugenie Bouchard remained and Bouchard still had to play her third-round match Saturday night.
Williams, the two-time defending champion, is the last American singles player left; there were 17 in the women's draw, and she's beaten three, including a 6-3, 6-3 victory against 2012 Olympic teammate and occasional practice partner Varvara Lepchenko.
Williams meets 50th-ranked Kaia Kanepi of Estonia, who knocked out No. 15 Carla Suarez Navarro 7-5, 6-0. Other women's fourth-round matchups: No. 11 Flavia Pennetta against No. 29 Casey Dellacqua, and Krunic against two-time U.S. Open runner-up Victoria Azarenka.
It's been an unusually difficult Grand Slam season for Williams, who lost before the quarterfinals at each of the year's first three majors. When a reporter asked whether it was important to get to the second week at the U.S. Open, Williams replied: "I mean, I can't believe I'm in the second week. It's like a dream come true for me at this point."
And to a follow-up question about why Williams couldn't believe it, she replied: "I'm being sarcastic."
Follow Howard Fendrich on Twitter at http://twitter.com/HowardFendrich
O Men's third and women's fourth round, Sunday, 9 a.m.
TV • Ch. 2
O Top-seeded Novak Djokovic beats American Sam Querrey 6-3, 6-2, 6-2, reaching the round of 16 at a 22nd consecutive Grand Slam tourney.
• Wimbledon champion and No. 3-seed Petra Kvitova falls to No. 145 Aleksandra Krunic 6-4, 6-4.