The Spanish great remains on course for an eighth championship in the Italian tournament at yet another clay court competition that he has historically dominated.
But after critically breaking his American opponent once in each set, Nadal was able to progress past the notoriously big-serving Isner in an hour and 19 minutes hours.
Nadal was never unduly troubled by Isner’s service games due to his ability to absorb the power and command returns on his favourite surface.
After the first four games were shared, Nadal created daylight by breaking at the third attempt in the opening set which never looked in doubt after that moment.
Isner’s seven aces and dangerous serving kept him competitive until Nadal moved 5-4 ahead in the second set with a stunning forehand return directly from the high-bouncing serve.
The Spaniard hit just three unforced errors en route to a sixth consecutive win over Isner.
While Nadal now meets the winner between Stan Wawrinka and Dominic Thiem in the next round for a place in the quarter-finals, he admits – at least publicly – he will be sitting on the fence when Real’s arch-rivals Barcelona take on Juventus in the June 6 final of Europe’s premier club competition at the Olympic Stadium in Berlin.
“I’ve lost a lot of times, and Real Madrid lost yesterday. That’s just part and parcel of sport,” said the Spaniard.
“I have a good friend at Juventus in Fernando Llorente – I will be happy for him – and also Alvaro Morata.
“At the end of the day, if Barcelona win I will be happy for them, but if Juventus win I will also be happy because I have friends there as well.”
In the meantime, Nadal said he was happy with his game but said he was not “consistent enough” to be considered the main favourite for Roland Garros next month, when he will bid for a record 10th title in Paris.
“I’m more than happy, I think I played a fantastic match against very, very tough opponent,” said Nadal.
“Today I did (moved better) and it seems like now I’m having more good days than bad days. The past few months have been on and off.”
Nadal has won the French Open at Roland Garros nine times but said his form on the red dirt so far this season means he won’t be the bookies’ favourite.
He added: “This year for sure I haven’t been consistent enough to be considered the main favourite for Roland Garros.
“Let’s see how I finish this week and then we can start to think about Roland Garros.”