Federer, who reigned supreme at Flushing Meadows with five consecutive titles from 2004, won the Cincinnati title last week on the back of reaching the final in Toronto and with world No.2 Rafa Nadal injured, many believe the 33-year-old Swiss maestro can claim an 18th grand slam title.
"Obviously not having to deal with (Nadal) is a huge positive for him potentially down the road if he's at a stage at the end of the event," McEnroe said in a conference call with TV channel ESPN for whom he will be working as a commentator during the year's final grand slam.
"I would give a slight, slight favorite to Djokovic based on it being best-of-five. He's younger and he can go the distance perhaps a little bit more easily than Roger at this stage. A little bit.
"Depending on what happens leading up to it if they were to play in the final, some of it would have to do with how much was left in the tank from previous matches."
Djokovic beat Federer in an epic Wimbledon final but the 27-year-old, who has just married long-time girlfriend Jelena Ristic, lost early in Toronto and Cincinnati and McEnroe believes the Serb has lost focus.
"I don't think Novak's mind has been into it since - it was one of the greatest matches I ever saw at Wimbledon," he said. "He got married. I didn't see a lot of his matches since, but I saw a few. I think it was difficult for him to get back into the swing of things. I believe he'll be ready here."
It is no foregone conclusion that Djokovic and Federer will contest the final, though.
McEnroe believes Briton Andy Murray, the 2012 champion, can use the U.S. Open to spark a long-awaited return to form, while he also tips Canada's Milos Raonic and Bulgarian Grigor Dimitrov to make strong runs on the New York cement.
Murray has not won a title since Wimbledon last year and has slipped to ninth in the world rankings, although he will be seeded eight in New York because of Nadal's wrist injury.
"I think that if you look at it, he's not that far away," McEnroe, a four-times U.S. Open champion, said.
"It depends if you only look at the glass half empty or half full, and people do both. But given the fact that he had a surgery on his back, which is pretty serious, if you look at his results at the majors, he wasn't that far off.
"He's putting himself in the position slowly but surely. To me, he's the third favorite to win this tournament. Depending on how the draw pans out, you would absolutely anticipate that he's going to be a factor in this event."
However, Australian Open champion Stanislas Wawrinka is struggling to back up his breakthrough moment and despite being seeded three, McEnroe is not expecting the Swiss to win a second grand slam of the year.
"He hasn't been the same since," McEnroe said. "He doesn't seem to be able to handle the attention in a way."
Federer will be playing his 60th consecutive grand slam at the U.S. Open - a feat McEnroe labels heroic.
"It's obviously remarkable and unbelievable that he's been able to do this consistently well for this long," said the American. "To do that, 60 majors in a row, is heroic in a way. It should not be underestimated or under-appreciated by tennis fans."
(Reporting by Martyn Herman in London. Editing by Patrick Johnston)