Tenth seed Keys, who had made at least the quarter-finals of her last three majors, lost in the third round 7-5, 5-7, 6-4 to Russian qualifier Evgeniya Rodina, ranked 120th in the world.
Keys' departure comes hot on the heels of early exits for two-time Wimbledon victor Petra Kvitova, 2004 All England Club champion Maria Sharapova, world number two Caroline Wozniacki and US Open title holder Sloane Stephens.
Serena gave birth to daughter Alexis Olympia in September, while Rodina became a mother to Anna in November 2012.
The 38-year-old American - last year's runner-up at Wimbledon - was the oldest entrant in the women's singles field.
Serena Williams in action against Viktoriya Tomova of Bulgaria during their third round match at Wimbledon on Wednesday.
Nadal won only 64 per cent of points on his first serve and faced 13 break points - including three in the first game of the match - but he saved 11 of them and converted five of his own to wrap up the win in under 2 1/2 hours on Centre Court.
Wawrinka, whose ranking has fallen to 224th following knee surgery, came from a set down to upset sixth-seeded Grigor Dimitrov in the first round for just his second Grand Slam victory since last year's Wimbledon. Isner had 113 aces in that match and Mahut hit 103.
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The 34-year-old Kohlschreiber is an accomplished player, having won eight career titles - twice the amount of Anderson - but he has never beaten the South African in matches on the ATP World Tour.
"Honestly, I think today was a massive mishandle of nerves", Keys said.
Struff was powerless against the Swiss' first serve and he couldn't deal with Roger's sharp and aggressive shots, unable to repeat a great match from the Australian Open when he stayed in touch with Roger despite losing in straight sets.
However, Cilic suffered a dramatic exit at the hands of Guido Pella on Thursday afternoon to fall early.
Seven-time champion Serena Williams reached the Wimbledon fourth round on Friday with a 7-5, 7-6 (7/2) win over France's Kristina Mladenovic.
Zverev had trailed two sets to one when his tie with Fritz was halted due to darkness on Thursday. She sat out Wimbledon a year ago while pregnant.