NEW YORK -- Andy Roddick's legs felt fatigued.
The crowd at Arthur Ashe Stadium was hushed.
And defending champion Rafael Nadal was at his court-covering, groundstroke-whipping, serve-stopping best.
Hardly a good combination for the last American man in the U.S. Open.
Overwhelming Roddick right from the start, Nadal compiled a stunning 22-0 edge in forehand winners, broke six times and never left the outcome of their match even remotely in doubt, winning 6-2, 6-1, 6-3 on Friday to reach the semifinals at Flushing Meadows for the fourth consecutive year.
What was it like for 2003 U.S. Open champion Roddick to be out there, his own game faltering and Nadal's as good as it gets?
"It's a bad feeling. It's almost worse than competing," Roddick said. "You feel helpless."
Nadal took the first four games in 18 minutes. He then reeled off 16 of the last 17 points -- including 12 in a row -- to close the second set.
"It was quick. Obviously, it was a combination of things that probably weren't going to work out today," said Roddick, who had trouble pushing off on serves and forehands and was massaged by a trainer during a medical timeout in the third set. "It was evident pretty early that he was in full control."
"It will be a very tough match for me," Nadal said, "and hopefully for him, too."
The other semifinal was set up by Thursday's quarterfinals, and it'll be a big one: No. 1 Novak Djokovic against No. 3 Roger Federer, who has won five of his record 16 Grand Slam championships at the U.S. Open. For the second time in the last three major tournaments, the final foursome is filled by the top men ranked Nos. 1-4 -- something that hadn't happened at the U.S. Open since 1992.
"They're pretty firmly the best players in the world right now," Roddick said. "They certainly deserve the numbers next to their names."
Djokovic is 62-2 with nine titles in 2011, including Wimbledon and the Australian Open. His first loss this season came when Federer ended Djokovic's 43-match winning streak in a thrilling French Open semifinal.
Nadal has won 12 of 16 career matchups against Murray, including eliminating him in the semifinals of the French Open on clay and Wimbledon on grass this year.
Now they'll meet on hard courts at the U.S. Open.
"It's a good surface for me to play him on," said Murray, who played 1½ hours longer than Nadal did Friday. "It's a close, close matchup."
The exits by Roddick and Isner -- with first lady Michelle Obama in sitting in the stands -- mean this will be the 32nd Grand Slam tournament in a row without a male champion from the United States, extending the country's longest drought, which dates to Roddick's 2003 triumph in New York.
The seats were mostly empty at the start of Murray-Isner, and the partisan crowd was oddly quiet watching Roddick succumb to Nadal.
"You'd rather be booed than have silence. It's an empty feeling," Roddick said. "That's one of the most disconcerting things. You don't ever want them to think you're giving less than you can."
Nadal didn't let Roddick do much.
One example: Roddick won only three of 10 points when he went to the net in the first set.
"That's the most aggressive I've seen him play this summer. He came out swinging," Roddick said. "He has a tendency to play himself into tournaments, and then by the end, he's taking cuts. I feel like today he was doing that."
Not all that long ago, the 29-year-old Roddick wasn't even sure whether he'd be able to compete at the U.S. Open this year because of a torn muscle in his side. Struggling with various injuries, the former No. 1-ranked man endured a tough season, and he dropped outside the top 20 for the first time in a decade.
At the U.S. Open, though, Roddick's serve was broken only a total of six times in four matches until Friday. Then again, he hadn't faced anyone anywhere close to the talent of Nadal.
Roddick, meanwhile, only threatened Nadal's serve once, at start of the third set, but the Spaniard saved all four break points there, the only four he faced all match.
Rain earlier in the week led the U.S. Tennis Association to delay the men's final from Sunday to Monday for the fourth consecutive year, and forced Roddick and Nadal on court for a third straight day. But only Roddick felt the effects, saying his sluggishness stemmed from a four-set victory over No. 5 David Ferrer on Thursday.
Murray, like Nadal one of tennis' top returners, weathered 17 aces at up to 140 mph from the 6-foot-9 Isner but repeatedly got back serves topping 130 mph and managed to break twice in a row bridging the first two sets.
"It's so frustrating playing against him because you feel like you're playing good tennis, and it's so hard to break him," said Murray, who has won his past 10 matches.
While Murray is a three-time Grand Slam runner-up, Isner was playing in his first such quarterfinal, and he acknowledged that jitters affected him at the outset.
"I wasn't swinging out like I felt like I should have early on in the match. I was just guiding the ball," said Isner, who lives in Tampa, Fla. "That was a little bit of nerves. It just took awhile to free up."
To date, Isner is best known for winning the longest match in tennis history, 70-68 in the fifth set in Wimbledon's first round in 2010, when he pounded 113 aces over its record 11 hours, 5 minutes.
Isner repeatedly has said he aims to be known for a more important victory in the late stages of a top tournament, but that'll have to wait.
"It's been a good run for me, but I'm still disappointed right now," Isner said. "I'm not satisfied."
Three-time major finalist Murray is only the seventh man in the Open era to reach at least the semifinals at all four Grand Slam tournaments in a single season. Three of the others: Federer, Nadal and Djokovic.
Trying to push Murray to a fifth set, Isner got the fourth into a tiebreaker, where his serving is usually a significant advantage.
Not this time.
Isner's play was littered with mistakes down the stretch: He double-faulted to trail 2-1, slapped what he later called a "gimme volley" into the net to make it 5-2, put a drop shot into the net for 6-2, then missed a forehand return on match point, ending things after 3 hours, 24 minutes.
"He put a ton of pressure on me," Murray said. "It was a relief to win that fourth-set 'breaker."
A key moment came when Isner held two break points while Murray served at 4-all, 15-40 in the fourth set.
On the first break point, Murray delivered a 129 mph ace. On the next, he hit a second serve that Isner thought might have been a fault -- it caught a line -- and Murray won the point with a stretching half-volley.
"I mean, how often does he make that shot? Probably not more than 50 percent," Isner said. "If I get that point there, I like my chances to serve it out. We'd still be out there right now."
Murray eventually held serve, although he clutched at the small of his back after one point. A game later, Murray's feet got tangled and he tumbled to the court. He quickly rose and afterward pronounced himself OK.
He'd better be, given what lies ahead against Nadal.