The second-seeded former world No. 1 Nadal routed 21st-seeded American Andy Roddick 6-2, 6-1, 6-3, while the world No. 4 Murray dismissed towering 28th- seeded American John Isner 7-5, 6-4, 3-6, 7-6 (7-2) in 3 hours, 24 minutes at Arthur Ashe Stadium.
Nadal, who has yet to drop a set at this fortnight, raced out to a 4-0 lead in the first set, including a pair of breaks against the big-serving Roddick, and simply sailed the rest of the way to the finish line on Day 12.
The second and third sets were all Nadal, as well, as the top-four seeds all reached the final four here this week. A hobbled Roddick nursed a left thigh injury in the lopsided setback and succumbed on Nadal's second match point, an easy forehand winner.
The dismantling was over in a brisk 1 hour, 53 minutes, as Nadal struck 20 more winners than Roddick (35-15) and broke the American a whopping six times. A gimpy Roddick failed to break his powerful left-handed counterpart.
The 25-year-old Nadal is now 7-3 lifetime against the 29-year-old Roddick, who topped the mighty Spaniard in the second round at the 2004 U.S. Open.
The 10-time major champion Nadal completed the coveted career Grand Slam by titling here in New York a year ago when he beat Novak Djokovic in the final.
Nadal is the reigning U.S. and French Open champ and has reached the semis at the last three majors. He'll now appear in his 17th career Grand Slam semifinal (13-3).
In the first quarterfinal on Friday, Murray seemed to assume control of the match by breaking the massive-serving Isner to grab a 6-5 lead in the first set. The Brit then consolidated the break and appeared to be on his way.
The Dunblane, Scotland native broke Isner again to open the second set and eased his way to another set win.
But Isner decided he wasn't going away. He opened the third set with a hold and then recorded his first service break of the day for a 2-0 edge. The American managed to hold his serve for the remainder of the stanza, which he won in surprising fashion to extend the bout.
A tight fourth set went to a tiebreak, which Murray dominated and closed out when Isner netted one final forehand return.
Murray could manage only two service breaks on Friday, while Isner settled for just one in a losing effort. The players combined for 31 aces, including 17 from the American.
"He put a ton of pressure on me," Murray said. "It was a relief to win that fourth-set 'breaker."
The steady Murray is the first British player in the Open Era (since 1968) to reach the semifinals at all four Grand Slam events in one season.
The 6-foot-9 Isner was playing in his first-ever Grand Slam quarterfinal. The 26-year-old was riding a nine-match overall winning streak, having recently titled in Winston-Salem in his native North Carolina.
Murray will now appear in his eighth career Grand Slam semifinal (3-4), which includes all four majors this year. The three-time Grand Slam finalist was this year's Australian Open runner-up to the high-flying Djokovic.
The 24-year-old Murray captured an ATP Masters event in Cincinnati last month by upsetting an injured Djokovic in the finale.
Nadal and Murray will meet for a 17th time at the ATP level, with the Spaniard holding a commanding 12-4 lead. Nadal is 5-2 all-time against the Brit in Grand Slam play, but Murray upset the Spaniard in the 2008 semifinals here in Flushing.
"I've beat him before in the semis; I won against him also at the Australian Open," Murray said. "And when I've won against him, it's always been on hardcourts. It's a good surface for me to play him on."
First Lady Michelle Obama was in attendance on a sunny Day 12 in New York.
"I've been trying to get to the U.S. Open my entire life," Obama said.
The current world No. 1 Djokovic and third-seeded former top-ranked great Federer will do battle in Saturday's other semi. Djokovic is an amazing 62-2 this year, including Grand Slam titles at Wimbledon and the Aussie Open. One of his 2011 losses came at the hands of Federer in the French Open semis back in June.
The 30-year-old Federer is 14-9 lifetime against the 24-year-old Djokovic, but the Serb has won three of their four meetings this season, including a win in the Aussie Open semis. Djokovic upset Federer in a magnificent five-set semifinal here in Flushing a year ago. The Swiss icon Federer, however, is 3-1 in their career U.S. Open matchups.
The last time the top-four seeds all reached the U.S. Open semifinals was back in 1992.
The newest U.S. Open champ will collect $1.8 million.