Isner completed a career Grand Slam of sorts, while Mathieu, a 30-year-old veteran, earned redemption after being the villain for France in the Davis Cup final in 2002.
First to Isner:
Much was expected from the 6-foot-9 American after his fine clay-court showings in 2012. There was that win over Roger Federer in Switzerland in the Davis Cup and another win on dirt against France's Jo-Wilfried Tsonga in Europe.
Supreme optimists even felt Isner could win the French Open, ahead of the likes of defending champion Rafael Nadal, world No. 1 Novak Djokovic and Roger Federer. But lukewarm preparation for the French left Isner with no confidence, and he succumbed to Mathieu 6-7 (2), 6-4, 6-4, 3-6, 18-16 in 5 hours, 41 minutes, the second-longest match in tournament history. And with it, the last American man was eliminated.
The second-round result meant that Isner has now gone past 6-6 in the fifth set of every single major, so the 70-68 marathon against another Frenchman, Nicolas Mahut, at Wimbledon in 2010 was far from an anomaly.
As you can imagine, Craig Boynton, Isner's coach, wasn't thrilled with the outcome. His head hung low.
Later, he offered his version of events.
"John lost early in Madrid, lost a match he really should have won in Rome and didn't play well in Nice, so coming into it he just wasn't playing great," Boynton told ESPN.com. "He didn't have the confidence you would need to go deep in a slam. But all the credit to Mathieu. Good for him."
Forty-one aces is an impressive number on clay, and Isner would be content with the way he served and got out of trouble. However, other parts of his game, and not for the first time, let him down.
Isner manufactured only four break points, compared to Mathieu's 24. Half of his 107 winners came courtesy of his serve, and he committed 98 unforced errors. Time and again, Mathieu exploited Isner's backhand, and the strategy worked.
Isner had two break points in the fifth but failed to convert. Mathieu then began pestering the Isner serve.
"[Isner] just wasn't returning well, and he was getting behind right off the get-go on the return points time in and time out," Boynton said. "On one of [two] break points in the fifth, he had a pretty good look at a forehand, and I think he just steered it. The other one, Mathieu hit a good serve. That was the only real chance he had in the fifth, and I think that kind of eats at him a little bit after time.
"But it's a feel-good story in France."
No one can argue about that.
The scenes near the locker room Thursday were entirely dissimilar to those 10 years ago, from a French perspective, when Mathieu lost the fifth match in the Davis Cup final to Russia's Mikhail Youzhny -- in Paris and on clay.
Mathieu's career, in his late 20s, was in jeopardy following a serious knee injury that required surgery. From the end of 2010 to the start of this year, he was off the circuit.
"I dreamed, that's why I fought," Mathieu said when asked if, during his layoff, he could ever win such a match. "These moments are indescribable. Today I was just happy to play again on this court. Even if I had lost, I would have spent an incredible day on the court, with all these people to encourage me."
When Mathieu returned from surgery, his coach recalled, he could barely hit a backhand.
"So to see what he did today, it's impressive," Jerome Potier said. "It's rapid [progress.] He's incredible at working. He doesn't need a coach. I never met a guy who was so easy to coach. It was a monster of a match between two warriors."
And on this day, it was Mathieu who stood taller.