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.
“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)
