World number one Djokovic, the hottest player in 2011 with a 57-2 winning record, was forced to quit the Cincinnati Masters final against Andy Murray when his weary right shoulder betrayed him.
Defending US Open champion Nadal, who completed the career Grand Slam with his victory in 2010, has endured a torrid summer since capturing a record-equalling French Open in June.
Early exits in Montreal and Cincinnati again prompted questions over the Spaniard's recovery from a left foot injury which had flared up at Wimbledon when he lost to Djokovic in the final.
Nadal's mood wasn't improved when he burned his fingers on his right hand in a Cincinnati restaurant.
Federer, meanwhile, is without a major since extending his record Grand Slam collection to 16 at the 2010 Australian Open.
With the great Swiss having celebrated his 30th birthday, and surrendered a two-sets lead to lose in five to Jo-Wilfried Tsonga in the Wimbledon quarter-finals, his career obituaries are already being penned.
But Djokovic, Nadal and Federer, having won 28 of the last 31 Grand Slam crowns, are still comfortably the favourites for a final which falls on the emotional 10th anniversary of the 9/11 terror attacks on the US.
"I've played so many matches this year," said Djokovic, this year's Australian Open and Wimbledon winner and the 2010 runner-up to Nadal at the US Open.
"Considering the schedule, it's kind of normal to expect that at some stage you are exhausted."
The Serb, whose only other defeat in 2011 was to Federer in the French Open semi-finals, which ended a remarkable 41-match winning start to the year, insists that his shoulder problem won't hamper his Flushing Meadows campaign.
Nadal is getting used to the questions he faces -- usually in relation to knees, ankles and feet -- before a Grand Slam.
On the eve of the French Open, he was widely expected to make way for Djokovic having lost to the Serb in all four finals of the opening Masters events of the year.
Two of those had come on the clay of Madrid and Rome, Nadal's sacred surface.
But it was the gutsy Spaniard who held aloft the Coupe des Mousquetaires for the sixth time -- equalling Bjorn Borg's record -- while Djokovic was licking his wounds after his loss to Federer.
"Tennis is a simple game. You don't have to think a lot what's going on. I have to be ready to play with high intensity and with my best rhythm for four hours," said Nadal.
Federer enters his 12th US Open, where he won five successive titles from 2004 to 2008, still believing he is a contender.
Since his French Open runner-up finish, Federer lost in the quarter-finals of Wimbledon before third round and quarter-final runs in Montreal and Cincinnati.
But he too is talking a confident game.
"I've had a good season in terms of playing enough matches, having enough practice, and being healthy. So I'm hoping that the end of the season is going to be strong," said Federer.
The lingering doubts over the world's top three will be good news for Britain's Andy Murray.
World number four Murray, under pressure to end his country's 75-year wait for a Grand Slam men's singles champion, was runner-up in New York in 2008.
The Scot was also runner-up to Djokovic at the Australian Open this year before losing to Nadal in the semi-finals at Roland Garros and Wimbledon.
"I can't wait to get started in New York," said Murray. "It's my favourite tournament."
Outside of the top four, the likes of America's Mardy Fish and giant Argentine Juan Martin del Potro, the 2009 champion, will be dangerous opponents.
Fish, the top American while Andy Roddick's form continues on a downward spiral, won the hardcourt title in Atlanta before finishing runner-up in Los Angeles and Montreal.
The 29-year-old was also a semi-finalist in Cincinnati, but has never got beyond the quarter-finals in New York, wary in his earlier years of Flushing Meadows' fast surfaces.
Del Potro became the first man to beat both Nadal and Federer at a Grand Slam event when he won in 2009.
He then missed eight months of 2010, including his New York title defence, because of a wrist injury.
Problems dog three kings of New York
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