The trio have dominated all major tournaments for well over a decade but Isner was able to win the Miami Masters earlier this year.
The big-serving American keeps getting better with age and he qualified for the ATP Finals for the first time in his career.
Isner was quizzed ahead of the tournament on if the Federer, Djokovic and Nadal are soon to be ousted by a new generation of winners.
But he thinks the top three players in the world will not slow down over the next 12 months.
'I won one and Sacha [Alexander Zverev] won two the year before, but he is not a newcomer in the winner's circle," Isner said.
'[Juan Martin] Del Potro has got to his first Masters final but we all know how good he is, he has got a Grand Slam [title].
'Last week Karen [Kachanov] played extremely well but he still had to beat Djokovic in the final.
'He had to beat the number one player in the world and he did that.
'I still think the old guard, Novak, Rafa and Roger, and when Andy [Murray] gets back healthy, won't be giving up the Masters titles too easily.'
Isner gets his ATP Finals campaign underway against Djokovic at
However, at 33 years old he is unsure of how many times he will get to play at the season-ending event.
'At 33 I certainly feel good but it doesn't get any easier at this age, it only gets tougher," he added.
'I think or me personally seeing a guy like Roger, he is a lot different, he is from another planet.
'He has done so many incredible things. At 37 it is encouraging for me to see him still at the very, very top of the game.
'It gives me a lot of incentive to keep working as hard as I can."