Murray ended Britain's 76-year wait for a Grand Slam men's champion by triumphing in New York in 2012 and backed it up with his historic Wimbledon victory this year, the first by a British man since Fred Perry in 1936.
The Scot beat Djokovic to win the US Open 12 months ago and repeated the dose against the Serb at the All England Club six weeks ago.
But it is Nadal, rather than Djokovic, who is tipped to win a second title in New York, to add to his 2010 victory, and clinch a 13th career major.
The 27-year-old Spaniard missed the 2012 tournament as he rested his troublesome knees, part of a seven-month injury lay-off which stretched from the second round at Wimbledon to Vina del Mar in Chile in February.
Since his return, Nadal has racked up nine titles, including five Masters, and boasts a win-loss record of 53-3.
His only blip was a first round trauma at Wimbledon, his bitter-sweet relationship with grass courts rekindled far too quickly after the draining march to an eighth French Open just two weeks earlier.
Nadal's title in Cincinnati last weekend followed victory in Montreal – the last man to clinch that double was Andy Roddick in 2003 who also went on to claim the US Open.
"It's a nice feeling to arrive to the US Open with two victories in two very difficult tournaments," said Nadal, never one to get too far ahead of himself.
"And it is nice to arrive there knowing that, if I am able to keep continuing, keep playing like this, hopefully, I have the chance to have a good result."
Nadal has supplanted Murray as world number two since Cincinnati after finding himself relegated to five when he reappeared in Chile.
Murray's post-Wimbledon party has fallen flat in recent weeks with a third round loss to Ernests Gulbis in Montreal followed by a quarterfinal exit to Tomáš Berdych in Cincinnati.
But Murray (26) has been here before – 12 months ago, he arrived in New York having suffered third round defeats in both Toronto and Cincinnati.
"The things I need to do well – serving, returning, moving – that was good," said Murray after his loss last week to the ever-dangerous Berdych.
Djokovic heads for New York with the focus squarely on Nadal as well as the worrying decline of Roger Federer.
The Serb, who beat Murray to retain his Australian Open title this year, came agonisingly close to ending Nadal's French Open domination in an epic Paris semifinal before being out-played by Murray in the Wimbledon final.
But the 26-year-old has made the US Open final in each of the last three years and is desperate to put behind him his quarterfinal loss to John Isner in Cincinnati, a performance he described as "terrible".
Djokovic, the 2011 US Open winner, is also keen to play down talk of how he and Murray – who have won seven of the last 11 majors – now hold the keys to the Grand Slam door.
"Hopefully that rivalry can develop over the years, but it's still not the biggest rivalry we have in sports. Out of all the active players, it's Federer and Nadal," said Djokovic, a loser in five sets to Murray in New York last year.
Federer heads into his 14th US Open at seven in the world, his lowest ranking for 11 years.
The 17-time major winner has already been defeated 11 times in 2013, including a second-round loss at Wimbledon which ended his record of 36 successive Grand Slam quarterfinal appearances.
In his desperation to stem the decline, the 32-year-old made the curious decision to play two low-profile clay court events after Wimbledon and even briefly experimented with a bigger racquet.
A five-time US Open champion, Federer's last final appearance in the city was in 2009 where he was defeated by Juan Martín Del Potro.
But despite his slump, the Swiss star believes he can still be a factor at the Grand Slams, a belief buoyed by having taken a set off Nadal in his Cincinnati quarterfinal defeat and the easing of a summer-long back problem.
"I know my body's fine and my mind's OK, so that's two good things looking ahead," he said. – Sapa-AFP