Isner left all four Grand Slam tournaments this year with five-set losses, and he didn't make it past the third round at any of them.
"It's disappointing," he said, staring down at the floor.
"I didn't play the right way, and that's been the story when I've lost at Slams," said Isner, at No. 9 the highest-seeded American man at Flushing Meadows. "I just played too passively and it doesn't work out when I do that."
The 19th-seeded Kohlschreiber won his sixth consecutive five-setter. The official completion time of this one was the same as a second-round U.S. Open match in 1993, when Mats Wilander beat Mikael Pernfors.
"Of course, it's very late, so everybody here is really a crazy tennis fan," Kohlschreiber told the few fans who remained during an on-court interview.
An earlier three-set victory by Maria Sharapova in Arthur Ashe Stadium was interrupted by a rain delay, and Isner and Kohlschreiber didn't start until after 11 p.m. Sunday. They played 3 hours, 20 minutes.
That length pales in comparison to Isner's record 11-hour, 5-minute victory that stretched over three days at Wimbledon in the first round in 2010, and his 5-hour, 41-minute loss at the French Open in the second round in May.
Isner departed the Australian Open in the third round in January, and Wimbledon in the first round in June.
Against Kohlschreiber, the 6-foot-9 Isner hit 22 aces, but he lost all three break points he faced. He only was able to break the German twice in 11 chances.
"I felt like the match was in my hands at one point there in the fourth set, and I let it get away," Isner said.
After that set, which ended at about 1:30 a.m., a sweat-soaked Isner headed to the locker room for a full wardrobe change, even switching shoes.
"It was really humid out there. As soon as I started playing, I knew that was going to be an issue," he said. "I always struggle when it's humid, and really from the get-go, I didn't have my legs."
That trip away from the court added a delay of about eight minutes. When Isner came back, his mood quickly soured.
In the first game of the fifth set, he got upset over a miscommunication when chair umpire Carlos Bernardes charged him for an instant-replay challenge that Isner said he didn't really want. After pushing a forehand long on the next point, Isner whacked a ball in anger into the stands, drawing a warning for unsporstsmanlike conduct.
Later in that game, a foot-fault call by a line judge that Isner disagreed with erased an ace and led to a double-fault. And after missing a forehand, Isner got broken to trail 1-0.
Two games later, now down 2-1, Isner re-aired his anger at that call, saying to Bernardes: "Who is this guy? How is he going to call a foot-fault? Worst call ever."
With that, Isner sat down in his changeover chair and pounded his racket to the court twice, busting up the frame then chucking it away. Because of the earlier warning, Bernardes charged Isner with a point penalty, so Kohlschreiber started the next game ahead 15-love. Nonetheless, Isner wound up getting a break point at 30-40, but Kohlschreiber erased that with a backhand winner down the line.
Isner got another break chance while down 4-3, but he sent a groundstroke long, and Kohlschreiber wound up holding to lead 5-3. Two games later, the match was over.
Isner now wants to "rest and rest and rest" before playing in the Davis Cup for the U.S. against Spain.
Next for Kohlschreiber is a match Tuesday against No. 8 Janko Tipsarevic, whose victory Sunday ended more than eight hours earlier.
Asked what the key for him will be moving forward, Kohlschreiber replied: "Recover as soon as possible."