Federer threatened a massacre before easing through to the quarter-finals of Wimbledon for the 16th time.
Federer defeated Mannarino 6-0 7-5 6-4 to reach the quarter-final of Wimbledon 2018.
His play already has fans and commentators dreaming of another final between Nadal and Roger Federer - on the 10th anniversary of their five-set classic that the Spaniard won.
They clapped and yelled when Federer's drop volley capped a 16-minute tour de force of a first set in which he won 21 of the first 23 points.
The win also allowed Isner, the highest-ranked US man, to have something about Wimbledon to relish other than his victory in the longest match in tennis history: 70-68 in the fifth set against Nicolas Mahut after 11 hours spread over three days in 2010.
'In the third set he started to play better from the baseline and I had couple of mistakes with the game I lost.
Three-time champion Djokovic, seeded 12, will next face Japan's 24th seed Kei Nishikori.
Del Potro was leading Simon two sets to one - 7-6 (7-1) 7-6 (7-5) 5-7 - when their fourth-round match was suspended under fading light. The grass isn't as slick as usual, the ball is bouncing higher, making the playing conditions more to Nadal's liking.
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Defending champion Roger Federer, who is more than likely to be playing in Sunday's final, even joked that maybe the World Cup final should move to accommodate the Wimbledon title match. His problem has always been the first week of Wimbledon, not the second week.
They then asked the ICC how good was Federer's effort, to which the global cricket governing body replied by putting Federer as the world's best batsman.
The victor of that clash will take on either Japan's 24th seed Kei Nishikori or unseeded Ernests Gulbis. She won the Australian Open and US Open in 2016 - becoming the first German to win a Slam since Steffi Graf in 1999 - and reached the Wimbledon final that year.
Rafael Nadal has breezed into his first Wimbledon quarter-final since 2011.
The 32-year-old also became the first South African man into the last eight at the All England Club since Wayne Ferreira in 1994. I think nerves are a great thing, it gets your system going.
The Swiss maestro swept away his opponent Adrian Manarinno in three sets, but it was a nonchalant flow of the racket in the third set which caught the eyes of willow-lovers.
(11) Angelique Kerber bt.
Beaten by Serena in the 2016 final, Kerber takes on Russian 14th seed Daria Kasatkina, a 6-7 (6/8), 6-3, 6-2 victor against Belgian world number 47 Alison Van Uytvanck.