Keys also came up short with a comeback attempt after fighting back from a set and two breaks down, losing 7-5, 5-7, 6-4.
The 36-year-old is bidding for a ninth title at the All England Club and maintained his fine progress through the opening week with a 6-3 7-5 6-2 win despite the best efforts of his German opponent.
Unfortunately, it was the Slovakian who was left dodging the majestic missiles that kept raining down on his half of the court.
Number three seed Marin Cilic suffered the shock of the day, slipping to a five-set defeat to world number 82 Guido Pella.
Four games into the second set, Mladenovic was hanging on desperately to her serve and Williams had the familiar air of queen of Wimbledon, where she has won seven singles titles, most recently two years ago before taking most of 2017 off for the arrival of her first child in September.
Highly-rated American Frances Tiafoe edged out France's Julien Benneteau 4-6 6-3 6-4 6-2.
Williams took to Snapchat moments before walking out on Center Court to share a few sweet videos of 10-month-old Alexis "helping" her mom get ready for the big game in the Wimbledon bathroom.
Djokovic overcame an apparent thigh problem to beat Horacio Zeballos 6-1 6-2 6-3, while top-ranked Nadal defeated Mikhail Kukushkin of Kazakhstan 6-4 6-3 6-4.
'What makes Roger and Rafa so tough to beat at Wimbledon is that, unlike a lot of the Tour events, the matches go to five sets.
"It's more hard for me to understand what's going on".
This is his 10th appearance at Wimbledon; he has reached the third round three times previously and lost.
Isner faced two match points against Bemelmans at 5-4 in the fifth set but held and then broke in the next game.
Nadal was warned again by Bernardes before the start of the third set.
German fourth seed Alexander Zverev takes on Taylor Fritz, the world number 68, who is bidding to reach the third round of a Slam for the first time.
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