World number one Djokovic takes on French 28th seed Jeremy Chardy who he has defeated six times in six meetings without dropping a set.
The pair's last meeting was in the first round at Wimbledon in 2011 when Djokovic cruised through for the loss of just six games on his way to his first and only title at the tournament.
The Serb has yet to drop his serve at Wimbledon this year, but having seen Roger Federer and Rafael Nadal both knocked out in the first three days, he is taking nothing for granted.
"It's sport. This is what happens. Everybody, especially lower ranked players in the opening rounds, have nothing to lose really when they go on the centre stage and they come up with their best game."
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Defending women's champion Williams and Japan's Kimiko Date-Krumm, two players with a combined age of 73, will clash in a battle of Wimbledon senior citizens.
Victory on Saturday will also give the American her 600th tour victory.
Date-Krumm, 42, has reached the Wimbledon third round 17 years after she last did so to become oldest woman to achieve the feat.