The players finally took to the court around 12.30pm (5.30pm BST) following poor weather that saw the whole of Tuesday's schedule washed out and a delay to the start of play on Wednesday.
Only the three main courts were able to start, with Nadal facing Luxembourg's Gilles Muller on Arthur Ashe Stadium, Murray meeting Donald Young on Grandstand and Andy Roddick taking on David Ferrer on Louis Armstrong.
But play was only possible for approximately 15 minutes before the rain began falling again. By that point Nadal was already 3-0 down, Roddick led Ferrer 3-1 and Murray and Young were on serve, with the American leading 2-1.
It quickly became clear the players were not happy about being asked to play when there was still moisture in the air, and Nadal, Murray and Roddick all went to see tournament referee Brian Earley to complain about the situation.
Defending champion Nadal was particularly strong in his criticism, telling ESPN: "They called us on court to start the match and the rain hadn't even stopped.
"I understand the fans want to see tennis but the health of the players is the most important and we do not feel protected. We want to feel good when we are playing a tournament and we cannot accept these things.
"We have to fight to change things, to have enough power that we don't have to go on court when it's raining. If I have to go on court, I'll go on court, but I don't think it's fair."
Organisers were particularly keen to get the fourth-round matches involving Nadal, Roddick, Murray and John Isner played because that section of the draw is a round behind.
Murray said: "When we went out on court it was still wet, and the balls too. It doesn't make sense to get out there for seven or eight minutes and I don't think that will happen again.
"I knew that Rafa was going to see (Earley). I said I would go in and mention it as well, then Andy (Roddick) came. It wasn't a party."
Roddick added: "I think if it's up for discussion, it's probably not playable. We wanted to make it known we probably didn't want to be put in that position again.
"It probably hits home a little bit more when there's three of us, not just one person being a little bit upset. I understand they need to put tennis on TV but first and foremost the players need to feel comfortable and safe."
The weather has played havoc at the US Open for the past three years, with the men's final being held on the third Monday each time, and, with the forecast for the rest of the week also poor, that again seems a distinct possibility.
Organisers are optimistic there could be play after 3.30pm on Wednesday, with the weather expected to close in again this evening.
The United States Tennis Association, which organises the tournament, issued a statement defending the decision to send the players out.
"All parties, including the players and tournament, want to get the US Open back on schedule," read the statement.
"As of 12 noon today, the best information available to us indicated the chance of a two-hour window without rain. Unfortunately, not all light rain and mist shows up on radar.
"We have experienced referees, and they decide if courts are fit for play. Conditions may be not ideal, but still can be safe.
"However, if a player or players feel that conditions are unsafe, we listen to them, as we have always done, and the referee uses that information as part of his/her assessment on whether to continue or halt play."
The rain did briefly cease and the process of drying the courts began but it was short-lived as the drizzle returned.
The decision was then made to cancel the men's quarter-finals that had been scheduled for Wednesday - the all-Serb clash between Novak Djokovic and Janko Tipsarevic and Roger Federer's much-anticipated rematch with Wimbledon conqueror Jo-Wilfried Tsonga.
Murray revealed there was already talk of a Monday final but stressed how keen the players are to resume their matches, provided the courts are safe.
He told Sky Sports: "The players more than anyone, especially on my half of the draw, are desperate to play because with each minute that passes its more of a disadvantage for us, potentially having to play four matches in four days.
"I don't remember the last time that would have happened in a slam and it's an incredibly difficult thing to do. We want to get out there, there's talk of maybe moving the final to Monday, which would help a little bit."
On that issue, the Scot added: "It depends if we get through the match today or not. If we don't, I think they should move it to Monday, but if not, just keep it as it is."