Spaniard Nadal has been ruled out of the final grand slam of the year at Flushing Meadows due to a wrist injury, so Djokovic has been installed as top seed.
And legendary American left-hander McEnroe, a four-time winner of the event, believes the world number one will take some stopping in the tournament which starts next Monday.
"Roger [Federer] looks great - he's looked the best of all the top guys this summer," said McEnroe.
"I think Novak had an incredible run at Wimbledon and it seems to me he is waiting for the Open.
"I don't think it matters a whole lot what's happened with his results in the summer. To me, he's still the favourite going in.
"There's a cast of other characters that will want to break through and finally put their names in the record books, and the most obvious ones are [Grigor] Dimitrov and [Milos] Raonic, but Djokovic is still the favourite."
McEnroe also believes it is time for Andy Murray to rise to the occasion in a tournament that he won two years ago.
"It's difficult to say what's happening with Andy," said McEnroe.
"It seems like the physical issues are behind him - it's impossible to say for sure from the outside but that's how it looks.
"It's been a process for him to come back from those issues so that takes its toll on the confidence, and he made a big change - I thought he and Ivan [Lendl, Murray's former coach] worked well together.
"To change course when he did is tricky so it remains to be seen what happens there. You need to give it more time to judge, but you sort of feel like the US Open would be a time he needs to step up because it's been a struggle compared to what it's been the last couple of years."