It was back to normal, meanwhile, for defending champion Roger Federer, who showed he was back at the top of his game by sweeping Arnaud Clement in straight sets to reach the fourth round in his bid for a seventh Wimbledon crown.
Marathon man Isner looked weary from the outset, required treatment for a neck injury and was beaten by unseeded Thiemo de Bakker of the Netherlands 6-0, 6-3, 6-2.
The second-round match was over in just 1 hour, 14 minutes, and the five games won by Isner is the fewest by a male player this week.
It was a complete turnaround from Isner's epic three-day victory over Nicolas Mahut, which lasted 11 hours, 5 minutes and went to 70-68 in the fifth set.
What's more, Isner served no aces after hitting a record 112 against Mahut.
"I've never been this exhausted before," Isner said. "Mentally and physically, I was obviously a bit drained. I just didn't have much in the way of my legs. I was just low on fuel out there. Didn't really have a chance."
Starting shortly after noon in warm sunshine, Isner received a standing ovation when he walked onto court. He immediately lost his serve - something that didn't happen once in his never-ending fifth set against Mahut.
"The turnaround time - he just didn't have enough time to get his body right," said Isner's coach, Craig Boynton. "He's one tired boy."
Federer looked perfectly fresh as he demolished Clement 6-2, 6-4, 6-2, playing like the old grass-court master himself after being stretched to five sets in his first-round match and four in the second.
Federer saved the only break point against him, hit 29 winners, made only 12 unforced errors and left Centre Court to a rousing standing ovation.
"I get standing ovations 99 percent of the time - doesn't matter if the performance was great or not so great," he said. "I think they're happy to see me, and they love tennis. ... But of course, when I end up winning, and they give me a reception like this, it feels good at the heart."
Federer will next play 16th-seeed Jurgen Melzer, who beat Feliciano Lopez in four sets. Federer and the Austrian played doubles together as juniors but have never faced each other in singles on the tour.
"I'm excited about having a weekend off, because it's been a tough first week," Federer said. "Not as tough as Isner and Mahut, of course, but still somewhat tough mentally. So I'm looking forward to Monday."
In women's play, five-time champion Venus Williams moved into the fourth round by beating Russia's Alisa Kleybanova 6-4, 6-2. Williams was down 3-1 in the first set before taking control with her power game as both players went for big shots from the baseline.
Williams took a tumble in the last game as she slipped on the grass, but appeared unscathed. The No. 2-seeded Williams next faces Australian Jarmila Groth, and could eventually meet top-ranked sister Serena in the final.
Justine Henin and Kim Clijsters - two Belgians making Wimbledon comebacks - won in straight sets to set up a fourth-round showdown Monday.
Clijsters, seeded eighth, beat No. 27 Maria Kirilenko 6-3, 6-3. Henin, seeded 17th, defeated No. 12 Nadia Petrova 6-1, 6-4.
Clijsters and Henin will play each other for the 25th time, but the first time in a Grand Slam since 2006. Their rivalry stands at 12-12 and has become friendlier over the years.
"It's obviously not the same as in the beginning," Clijsters said. "We've definitely grown up. We've had great times together playing Fed Cup and just messaging each other on phones, teasing each other, fun, you know, relax. I think that's how I would have liked it to have always been."
Both Belgians have mounted career comebacks from retirement. Clijsters last played at Wimbledon in 2006, Henin in 2007. Henin has seven Grand Slam titles and Clijsters two, but neither has won the Wimbledon crown.
Clijsters won their last previous meetings this year in Brisbane and Key Biscayne.
No. 4 Jelena Jankovic beat No. 28 Alona Bondarenko 6-0, 6-3. No. 11 Marion Bartoli, the 2007 runner-up, defeated Greta Arn 6-3, 6-4.
No. 3 Novak Djokovic reached the round of 16 by beating No. 28 Albert Montanes 6-1, 6-4, 6-4.
That sets up an intriguing fourth-round battle against 2002 champion Lleyton Hewitt. The 15th-seeded seeded Australian, enjoying a resurgence after returning from hip surgery, advanced with a 6-3, 7-6 (9), 6-4 win over Frenchman Gael Monfils.
Hewitt saved three set points in the second-set tiebreaker, and pumped his right arm four times in celebration after closing out the set. Monfils fought back to stay close in the third but double-faulted to end the match.
In a minor upset, 13th-seeded Mikhail Youzhny of Russia was ousted by Paul-Henri Mathieu, 6-4, 2-6, 2-6, 6-3, 6-4.
Isner didn't warm up before taking the court and showed up unshaven. He dropped the first set in 16 minutes, winning only nine points while committing 11 unforced errors.
"It was brutal," Isner said. "Things were looking pretty bleak right from the get-go."
After the set, he took an injury timeout and received a neck massage from a trainer. Boynton said Isner's neck began to stiffen after the Mahut match.
Following the loss, Isner pulled out of doubles before his first-round match with partner Sam Querrey, citing fatigue and a blister on his small left toe.
"Your body's like, 'Hey, what are you doing to me here?'" Boynton said. "I mean, that match seemed like it was two weeks long."
The crowd roared on Court 5 when Isner finally won a game after 32 minutes to trail 2-1 in the second set. His shots began to show more zip, but his movement remained sluggish. Several times he didn't even pursue shots, and when he buried a forehand in the net in the third set, he bent over with his hands on his knees.
Seeing the toll the marathon took on Isner, de Bakker said he felt sympathy.
"Of course," de Bakker said. "I mean, 70-68, it's pretty sick. People at home who didn't know it, watching it, I mean, they'll probably think it's a mistake. It's unbelievable."
