She missed last year's tournament while pregnant.
Federer played first on Wednesday, then came Serena. I thought I did very well today.
The 38-year-old American - last year's runner-up at Wimbledon - was the oldest entrant in the women's singles field.
The Israeli tennis star Dudi Sela was beaten Tuesday by world number one Rafael Nadal in the first round of the Wimbledon Grand Slam tournament, in his third loss to the Spaniard in three career matches.
The Croat was stunned 3-6 1-6 6-4 7-6 (7-3) 7-5 by Argentina's world No.82 Guido Pella in three hours 12 minutes.
There was a fine and predictable magic to all of this in the late afternoon, another afternoon at the 2018 Wimbledon when Serena Williams and Roger Federer were sharing Centre Court, the way they did the other day. Keys and Williams now join Caroline Wozniacki, Garbine Muguruza, Sloane Stephens, Elina Svitolina, Caroline Garcia and Petra Kvitova as top 10 players eliminated before quarterfinals.
For Williams, losing the first set was nothing unusual at Wimbledon this year after she battled back to win her opening two matches following the same deficit.
South African eighth seed Kevin Anderson and Frenchman Gael Monfils also reached the final 16 on Friday.
Defending champion and top seed Federer, by contrast, has made the third round without breaking sweat.
Serena Williams ran her Wimbledon winning streak to 17 matches and moved into the fourth round with a 7-5, 7-6 (2) victory over 62nd-ranked Kristina Mladenovic of France, thanks in part to 13 aces.
John Isner, the USA ninth seed, saved two match points, fired 64 aces and 88 winners to defeat Belgian qualifier Ruben Bemelmans 6-1, 6-4, 6-7 (6/8), 6-7 (3/7), 7-5.
The world number 64 has had to fight back from two sets to love down in his first two matches to beat Leonardo Mayer and 39-year-old Ivo Karlovic.
"I'm happy I found a way today".
Dominic Inglot and Franko Skugor came through to win 6-3 4-6 7-6 (7-5) 2-6 6-2 in five sets against Fernando Gonzalez and Marcelo Demoliner.
They traded breaks mid-set and Mladenovic did well to hold from 15-40 in the 10th game - just seven points from going out of the tournament.