Whipping passing shots from all angles and returning superbly, the No. 2-seeded Nadal beat No. 21 Roddick 6-2, 6-1, 6-3 to reach the semis at Flushing Meadows for the fourth consecutive year.
The Spanish star compiled a stunning 22-0 edge in forehand winners and broke Roddick's powerful serve six times.
"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 his fatigued legs 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."
Nadal took the first four games against the 2003 U.S. Open champion thanks to two breaks in the opening 18 minutes, then took 16 of the last 17 points to close the second set. In the third set, Roddick had both of his legs massaged by a trainer during a medical timeout.
"The beginning of the match was really important," Nadal said. "Andy had a really tough match yesterday. Probably, he was tired. Sorry for him."
Seeking his 11th Grand Slam title, Nadal has yet to drop a set heading into Saturday's semifinal against Britain's Murray, who beat No. 28 John Isner 7-5, 6-4, 3-6, 7-6 (2) earlier Friday.
The other semifinal was set up by Thursday's quarter-finals and will feature 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 four men in the game — but it hasn'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 at 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 matches against Murray, including a win in the semifinals of the French Open and Wimbledon this year.
Murray figures to face more of the same trouble in New York if Nadal plays as well as he did Friday.
"It will be a very tough match for me," Nadal said, "and hopefully for him, too."
The exits by Roddick and Isner — with first lady Michelle Obama sitting in the stands at Arthur Ashe Stadium — 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.
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 abdominal muscle. Struggling with various injuries, the former No. 1-ranked player has endured a tough season, dropping outside the top 20 for the first time in a decade.
At the U.S. Open, though, Roddick's serve was broken only six times in four matches until Friday. Then again, he hadn't faced anyone anywhere close to the talent of Nadal.
Early in the second set — after Roddick was broken yet again — seven-time major champion John McEnroe said on the CBS broadcast: "So far, he looks like he's in slow motion."
A couple of games later, Roddick double-faulted to get broken at love and fall behind 4-1 in that set.
Roddick, meanwhile, wasn't able to threaten Nadal's serve until the start of the third set, but the Spaniard saved all four break points there — the only four he faced all match.
Similarly, Murray dealt well with Isner's big serve, ending the marathon man's best run at a major tournament.
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. "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 five 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."
Murray's past Grand Slam final appearances include losses to Djokovic at the Australian Open in January and to Federer at the U.S. Open in 2008. He's seeking to become the first British man since 1936 to win a Grand Slam title.
As it is, 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 are 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."