Top seed Djokovic, untroubled so far as he seeks a sixth Australian Open title, takes on Italian 28th seed Andreas Seppi having beaten him in all 11 of their previous meetings.
Williams resumes her pursuit of a seventh crown at Melbourne Park against Russia's Daria Kasatkina after fifth seed Maria Sharapova takes on 22-year-old American Lauren Davis.
Djokovic will be happy to be back on court after his serene progress was interrupted in his post-match media conference on Tuesday when he was forced to deny allegations in an Italian newspaper about match-fixing in 2007.
He will be wary though as Seppi beat Roger Federer at exactly the same round of last year's Australian Open.
