Like Nadal, who could strike Djokovic in the semis, Federer hasn't dropped during his charge to a 16th Wimbledon quarter-final, nearly surely a staggering record that will never be surpassed.
Del Potro fell 4-1 behind in the third set after Simon broke in the third game.
Here's how the last eight men standing match up.
Top seed Federer, 36, has now won 32 consecutive sets at Wimbledon, just two behind his record set from the 3rd round in 2005 to his title triumph in 2006.
The Frenchman was not embarrassed in the third set either as Federer settled for a single break of serve to close out the match. It's like today, I hope I get off to a good start, go from there. With the first set done in the blink of an eye, the £120 ticket looked like it wasn't going to be giving great value for money but Mannarino did eventually settle down in the second and made it somewhat competitive. That it happened to be in straights, it helps me for the season and to save energy for the rest of the tournament.
(12) Novak Djokovic bt.
Anderson is yet to win a set in four previous meetings with the Swiss maestro but in the three years since they last met he has developed his all-round game to such an extent that he reached last year's U.S. Open final, losing to Rafael Nadal. "I feel physically, mentally ready, fit, positive".
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By no means are they assured a spot, as world No. 7 France , who oddsmakers are favouring, stand in their way. We don't realise the support we're receiving like we did at the European Championships.
The only player with a superior head-to-head record over both grand slam giants, Djokovic has warned he's finally approaching his own brilliant best after an utterly unexpected two-year major title drought. "It's always a big challenge".
"It's true it has been a while", Nadal said about his return to the last eight.
Del Potro was leading 7-6 (7/1), 7-6 (7/5), 5-7 when his tie with Simon was halted for the night due to darkness.
A pretty emphatic win against an opponent who had no answers on the day, Fed had too much pace of shot, too much guile and too much aggression.
The top-ranked Spaniard is back in the quarterfinals at the All England Club for the first time since 2011 - and playing a lot like the man who reached his fifth final that year.
"It will be a different match that we played in Paris a few weeks ago", Del Potro told reporters. Hopefully, it doesn't come full circle and my gloating come back to haunt me in the shape of Anderson playing lights out! I just tried to fight for every point.
Del Potro trails Nadal 10-5 in head-to-head meetings - his five wins all coming on hard courts.