Murray, aching to register his first grand slam triumph and the first for a British player in 75 years, booked his spot in the semi-finals at Flushing Meadows with a four-set win on Friday against big-serving American John Isner.
That victory, clinched 7-2 in the fourth-set tiebreaker, moved Murray into his fourth successive grand slam semi-final this year.
Standing in his way is a familiar opponent.
The 24-year-old Scotsman lost to Nadal at the French Open and Wimbledon semi-finals and trails the Spaniard 12-4 in career meetings, but Murray is confident on the hard court.
"Well, I've beat him before in the semis," noted Murray, who overcame Nadal on his way to the 2008 U.S. Open final.
"I won against him also at the Australian Open," the Briton said, referring to a quarter-finals test last year. "And when I've won against him, it's always been on hard courts. It's a good surface for me to play him on."
Murray is 3-3 against Nadal on hard courts dating back to 2008.
A three-time grand slam finalist, Murray is trying to become the first Briton to win a grand slam singles crown since Fred Perry won his third U.S. Open in 1936.
Murray did what he had to do to blunt the ferocious attack of towering 6-foot-9 (2.06 m) Isner.
"It may look like you're playing defensively or whatever, but it's not the case," said Murray, who at times had seemed content to trade groundstrokes and wait for Isner errors.
"You can't take chances against someone that's serving 140 miles an hour ... You've just got to try and find a way to win, and I did that."
Murray needed three hours 24 minutes to eliminate Isner and will have to bounce back Saturday to play Nadal in a schedule compressed due to back-to-back wash-outs this week.
"I'm feeling fine now. A lot of times that's the case. It's kinda how you wake up the next day," Murray said.
"It was hot today. It was a pretty long match. You know, it's not like you are you into a classic endurance when you play against him. You have to be so explosive.
"You're not like having 30-shot rallies that you might have against Rafa. You're having to react all the time and stretch for balls and chase down like drop volleys. It's a different sort of fitness against him.
"I think on the American hard courts, it's a close, close match-up," he said.