Both arrived in New York with question marks over injured left wrists, but seemingly have put the issue behind them.
If they survive two more matches, a semi-final encounter awaits, with Djokovic holding a 26-23 head-to-head career record.
World number one and defending champion Djokovic, who takes on Briton Kyle Edmund, has played just one full match due to injuries by his second and third-round opponents. He understands the pros and cons of lack of court time.
“As you are approaching the second week of a grand slam you want to have match play and you want to have time spent on the centre court before you face one of the top players," said the Serbian.
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“But I'm not too concerned about my game itself. I've worked hard the last couple days and health-wise I feel much better than I did at the beginning of the tournament. I’m confident that everything is going in the right direction.”
Nadal, who missed Wimbledon with a wrist injury that forced him to quit after two rounds of the French Open, has not dropped a set on his way to the last 16, building on his run to the semi-finals at the Rio Olympics, where he won a gold medal in doubles.
“I don't know in which kind of level I am,” said the fourth-seeded Spaniard, who takes on 24th-seed Lucas Pouille of France.
“It is true that when I had to stop I was playing great. I felt myself ready for the French.
“For me it is great news that I am on the tour again and I am playing every day with less pain on the wrist. That's the most important thing.”
In women's action, second seed Angelique Kerber plays two-time Wimbledon champion Petra Kvitova for a quarter-final spot, while 2015 runner-up Roberta Vinci faces Lesia Tsurenko.
(Editing by Andrew Both)
