But not by the most likely candidate.
Andy Roddick, the No. 5 seed and a sentimental favorite here, was upset 7-6 (3), 6-3, 3-6, 5-7, 7-6 (5) by fellow American John Isner in a third-round match which started Saturday afternoon and ended nearly four hours later under the lights at Arthur Ashe Stadium.
"I'm happy for him," Roddick said. "I'm mad that it came at my expense."
Playing before a delirious crowd -- while masses of ticket-holders for the night session patiently waited behind closed gates and watched on giant overhead screens outside -- Roddick made an inspired comeback from two sets down to force a decisive fifth set.
But the 55th-ranked Isner won the fifth-set tiebreak -- earning the only service break with a crosscourt backhand winner from 10 feet behind the baseline -- to finish off the biggest victory of his career in three hours and 51 minutes.
"I played the match of my life to beat him on that stage in that setting," said Isner, who became the first American to defeat Roddick at the U.S. Open since Pete Sampras in 2002.
The 6-foot-9 Isner, who pounded a career-high 38 aces past Roddick with a serve that clocked as high as 140 m.p.h., used a booming serve and aggressive play to stake a surprising two-sets-to-none lead. He made 67 net advances to Roddick's 27, and converted 63 percent of them.
"There's a lot that's out of your hands with the way he plays," Roddick said. "You can't really teach 6-foot-9, especially coming down on a serve."
Two times in Roddick's career had the five-time Grand Slam finalist come back from two sets down to win a match, including once against David Nalbandian during his run to U.S. Open title in '03. And it seemed like Saturday might be the third, as Isner -- who missed three months earlier this season during a bout with mononucleosis -- fought cramps and seemed to fade during the later stages.
But the 55th-ranked Isner was able to make it through the fifth set and force the tiebreak, a situation where he's thrived, winning 16 of his last 17.
"I knew I wanted to finish it before it got to a tiebreaker and became a shootout, but it didn't happen." Roddick said.
Six Americans reached the last 32 of this year's U.S. Open, the host country's best performance here since '03. Now an event that's had the feeling of a revival meeting for American men's tennis moves on without its most recognizable figure.
Isner advances to a fourth-round match Monday against No. 10 seed Fernando Verdasco, who survived an earlier five-setter against Tommy Haas earlier in the afternoon.
Roddick needed to dig deep just to force a fifth set. Serving at 5-4, 30-30 in the fourth, Roddick committed his first double fault of the match to move to the brink of defeat. But he saved the match point with a 122-m.p.h. ace and went on to win the game.
After rattling off four straight points in the ensuing game for a crucial break, Roddick held serve to force the fifth set, where the two opponents held all the way to the tiebreak.
The unseeded American prevailed in just the second five-set match of his career despite committing 52 unforced errors, more than twice Roddick's total (20).
Isner has long survived on the strength of his booming serve, since joining the tour in 2007 after leading the University of Georgia to the NCAA championship.
But the Greensboro, N.C., has made strides in his mobility, groundstrokes and net play over the past year and his results have reflected the improvements. Isner made the semifinals at Indianapolis and Washington and saw his ranking climb to a career-high No. 55 in August.
He entered Saturday's match with a 2-6 record against Top 10 players with both victories coming this year -- against No. 9 Gael Monfils at the Indian Wells Masters and No. 7 Jo-Wilfried Tsonga at Washington.
Roddick remains the last American winner of a major men's singles title. The 23 Grand Slams since his '03 U.S. Open victory is the second-longest gap between major victories for U.S. men after the 31 majors that elapsed between Tony Trabert's win in the 1955 U.S. Open and Chuck McKinley's victory at Wimbledon in 1963.
He entered this year's tournament as the romantic favorite after an inspired runner-up finish at Wimbledon, where he lost another epic five-set match against Roger Federer in the final.
"I've never come into a Slam with as much confidence as I did with this tournament and I'm leaving earlier than I want to," Roddick said. "The times I've lost early, it's been a little dicey coming in.
"It's just the way tennis is: the fact that I was able to make a quarterfinal last year and I was playing just terrible and didn't make it past the third round this year."