Djokovic was hardly tested in his first two matches, winning both in straight sets, and the 2011 champion will be highly fancied again against unseeded Querrey, the world number 57.
Querrey will be looking to continue the form he displayed when he eliminated 28th seed Guillermo Garcia-Lopez of Spain in the second round.
On the women’s side, it will be the third successive match that Williams has faced another American. The defending champion dropped only five games in total in her first two matches, and has also dominated world number 52 Lepchenko in their previous two head-to-head clashes.
In the evening session, seventh seed Eugenie Bouchard will be back in action less than 48 hours after surviving a tough three setter against Sorana Cirstea.
Next up for Canadian Bouchard is 30th seed Barbora Zahlavova Strycova. Bouchard took three sets to beat her Czech opponent when they met in Japan last year in their only previous hardcourt encounter.
The center court nightcap will pit 16th seed Spaniard Tommy Robredo against big-serving Australian teenager Nick Kyrgios, who reached the quarters at Wimbledon two months ago and is ranked 60th in the world.
Robredo was taken to five sets in the second round, while Kyrgios has dropped only one set in his first two matches.
(Reporting By Andrew Both in Cary, North Carolina; Editing by Peter Rutherford)