Federer holds the record for Grand Slam titles in the Open era with 17 but he will start the US Open as seventh seed – his lowest seeding in 11 years.
McEnroe, who won seven Grand Slams himself and now commentates on the sport, said he thinks it might just be the beginning of the end for Federer who has won only one Grand Slam (Wimbledon 2012) since 2010 and who is now 32.
"To me, it's obviously going to be a lot more difficult at this stage," he said.
"I don't see at this stage him being able to go through all seven (rounds) and have to beat at least two of these three guys.
"There are certainly scenarios where he could easily still get late into an event and even to a final.
"Andre (Agassi) got to the final of the Open at 35, so there's no reason to believe he couldn't do it.
"At Wimbledon I could see him going late into an event, a final. I could see it on a hard court...but I personally think that at this stage it's going to be quite, quite difficult for him to win another one."
The US Open starts on Monday with Federer potentially facing Rafael Nadal in the quarter-finals.