Eight-time champion Federer, four-time winner Djokovic and Nadal, a double champion, all play last 16 ties against opponents who have never progressed this far before, AFP reported.
Federer, the second seed, tackles Italy's world number 20 Matteo Berrettini in what will be the Swiss great's record 17th fourth round appearance at the All England Club.
"I don't know him very well, so that makes it a bit more tricky," said Federer, chasing a 21st Grand Slam title.
"I saw him play a little bit in Halle (where he made the semifinals). Saw his run, of course, in Stuttgart (which Berrettini won).
"Now he's backing it up here again. That's not easy to do, especially when you're sort of newer on the tour."
Nadal, the champion in 2008 and 2010, also has an unexpected opponent in the shape of world number 69 Joao Sousa, the first Portuguese player to reach the fourth round at Wimbledon.
Nadal has a 2-0 career advantage over the 30-year-old Sousa, with both wins coming on clay.
"He's a super dangerous opponent against everybody. He is very quick, has a very good physical performance," said Nadal, looking to back up his 12th Roland Garros title last month with a third Wimbledon.
Grass court rookie
Djokovic insisted he will not be complacent about his chances of reaching the final for the sixth time.
The highest seed that the world number one can face before the final is number 15 Milos Raonic, the 2016 runner-up from Canada.
But first up for the defending champion and 16-time major winner is 21-year-old Ugo Humbert from France who is playing in his first Wimbledon.
"There were a lot of top seeds that went out in early rounds in Wimbledon," said Djokovic.
"That's why these kind of tournaments are regarded as the most important events where you always come out with your best game."
Until this year, world number 66 Humbert had never played a grass court match either as a junior or professional.
However, he has knocked out two seeds to get this far.
He saw off compatriot Gael Monfils, the 16th seed, through a first round retirement and then 19th seeded Canadian Felix Auger-Aliassime in straight sets in the last 32.
Should Djokovic emerge triumphant, he would face either Belgian 21st seed David Goffin or Spanish veteran Fernando Verdasco in what would be his 11th quarterfinal at the tournament.