It was the main stadium at Flushing Meadows until the cavernous Arthur Ashe court opened in 1997 and has an illustrious history, but Murray must feel like there is Kryptonite under the surface.
He suffered his last early defeat at a grand slam there in 2010 against Stanislas Wawrinka, and struggled through matches with Robin Haase in 2011 and Feliciano Lopez and Marin Cilic last year.
This time Argentina's world number 81 Leonardo Mayer was the foe to cause Murray trouble, with the defending champion extended to four sets in round two before clinching a 7-5 6-1 3-6 6-1 victory.
Murray said: "It's a court I haven't played my best tennis on, that's for sure. And I think the conditions, well, it's day and night, isn't it? It's completely different.
"The ball was bouncing extremely high out there at the beginning, and he's a big hitter of the ball. He served big, too, bigger than I thought. Big second serve, too. It took me some time to get used to his game.
"I've had some tough matches there in the past, and today was the same."
Murray may wonder what he has done to upset tournament organisers after following up his late-night start on Wednesday by becoming the first of the big names exiled from Ashe to Armstrong.
He insisted that did not bother him, saying: "I'm happy to play on any court. It doesn't really make a huge difference. We got a great crowd out there. It was a really good atmosphere from pretty much the first point through to the last.
"Whether or not I've played well on that court, it's always a really good atmosphere."
Murray said after his first-round win over Michael Llodra that Mayer, who is exactly the same age as the Scot, was ranked below where he should be because of injury, and the Argentinian quickly set about proving him right.
His forehand was the key weapon of the match and he showed a willingness to attack that had Murray immediately on the back foot.
Mayer had break points in the first game, but Murray served his way out of trouble, and was then handed the first set when his opponent suddenly threw in a shocking service game.
The second set was one-way traffic but Mayer roared back at the start of the third with more big forehands, and held his nerve impressively to win the set.
Murray was almost overwhelmed with frustration but let out a huge yell of 'come on' when he broke to lead 3-1 in the third, and the end came swiftly after that.
The Scot said: "I was a bit frustrated at points in the match because I was doing quite a lot of the running for a lot of it. I wasn't getting much depth on my returns, so when he was serving I was having to do a lot of running.
"I served a low percentage (of first serves). I served pretty well in my first match, and then today struggled to control the first serve.
"So I was playing a lot of points on my second serve. When that happens, you have to do a lot of the running. You don't feel like you're dictating the match. It can be frustrating."
Murray's next opponent is Mayer's namesake, Florian, a German ranked 47th in the world who Murray has beaten in both their previous meetings.
Laura Robson opened proceedings on Ashe but could not repeat her heroics of last year as she went out 6-2 7-5 to sixth seed Li Na, who she had beaten at the same stage 12 months ago.
Since then 19-year-old Robson has more than halved her ranking and was seeded for the first time here at 30, but she admitted she had hoped to have made even more progress.
Robson said: "I feel I'm a more confident player. In my first two rounds I thought I played really well and I closed out the matches really well, which is something that has improved a lot over the last 12 months.
"I would say I set my expectations quite high, so for me it's still quite disappointing.
"I would love to be more consistent at the smaller tournaments. So that's what the plan is for Asia.
"But I think I have a lot to work on, and I think I can improve a lot more. Hopefully in the next few months I won't still be around 30."
First Robson will take a break to recover fully from her wrist injury and have her wisdom teeth out before heading to China, where she reached her first WTA Tour final last year.
On Saturday, Dan Evans will attempt to continue his incredible run with victory over 19th seed Tommy Robredo in the third round.
It will be a first match on a big stadium court for the 23-year-old qualifier from Birmingham, who will take to Armstrong for the final contest of the day.
Murray revealed he has been helping out with advice on Evans' opponents and is hoping to watch some of the match.