Anderson, the first South African to reach the last eight since Wayne Ferreira in 1994, was steadfast though and did what no man had done at Wimbledon since last year's semi-final when he broke Federer's serve early in the second set.
"It's one of those average days you have to try to win the match, and I just couldn't get it done". "I nearly could have".
Next up for the American will be Milos Raonic, who overcame Isner's countryman Mackenzie McDonald 6-3, 6-4, 6-7 (5/7), 6-2.
There was still the small matter of holding serve but a 28th ace helped settle Anderson's nerves and be brought up match point with a massive forehand before completing a remarkable victory with a first serve that Federer could not handle.
The comeback was just beginning. "It's not like I would have remembered exactly how it would have felt", he said.
But the big-serving and obdurate Anderson was undaunted by the situation, staying alive before turning the tide in his favor, preventing Federer from breaking his own record for consecutive sets won at SW19.
Kevin Anderson did the unthinkable on Wednesday, rallying from two sets down against the always great Roger Federer in a grueling Wimbledon quarterfinal match to advance to his first semifinal. "When I come here, I come here thinking I can do a good result".
Federer was 4-0 against Anderson entering the day, winning every set they'd ever played against each other. But there was more.
But if the IL men's tennis coach could chime in with a piece of advice for one of his former Illini standouts, he'd offer up the following before Kevin Anderson faces Roger Federer in the quarterfinals at Wimbledon.
The 12-time Grand Slam champion's confidence has been on display over the first four rounds.
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"His consistency, the way he plays such great tennis week in and week out", said Anderson.
"If you go out there with doubts or unsure what's going to happen, like I maybe did a little bit in that first set, it's not going to go your way". The eighth seed though will be confident, given the way he has performed in major tournaments in the recent past - a run that includes US Open 2017 runner-up finish. Djokovic broke Nishikori's serve seven times, and finished with six aces.
Anderson then served it out, ending things with a 128 miles per hour service victor, and raised both arms overhead.
"I feel like a lot of aspects of my game can give him a lot of trouble", said Anderson, the first South African man in the Wimbledon quarter-finals since Wayne Ferreira in 1994.
Novak Djokovic wasn't definitely happy about having to play on No. 1 Court as third and last match of the day on Monday. That earned a code violation from chair umpire Carlos Ramos.
"I think the grass is flawless for Djokovic this year, it helps his backhand", he said.
Later, Ramos warned Djokovic for a time violation, but that didn't seem to faze the Serb.
Novak Djokovic's clash with Kei Nishikori and Rafael Nadal's duel with Juan Martin del Potro share the Centre Court limelight. "I've put myself in with hopefully a shot to be playing again on Sunday". "I don't want to stop here".
'I don't think it really mattered, to be honest.