Despite struggling in the brutal heat and humidity at times, Djokovic swept past Joao Sousa in straight sets on Monday to continue his quest for a third US Open title.
The Serb received a medical timeout against Sousa but has been coy when asked about the reasons why and that is the only question mark hanging over him at the moment.
He has already beaten Millman this year when they met on the grass at Queens in what was a one-sided affair, but he will be expecting a tougher challenge here with his opponent on a high after eliminating Roger Federer last time out.
World number 55 Millman has been the surprise package at Flushing Meadows this year and produced arguably the best performance of his career in defeating five-time champion Roger Federer in the fourth round.
Although the punishing humidity was a major factor in Federer's below-par performance in that match, the Australian proved that he can cope with such conditions and he will be hoping for similar against Djokovic, who has struggled in the heat himself.
This is uncharted territory for the 29-year-old having never previously progressed beyond the third round of a major and the focus will very much be on whether he can maintain the standards he reached against Federer.
Millman will undoubtedly be carrying confidence from his shock fourth-round win but a key factor behind that success was the fact that a struggling Federer played nowhere near his best and made an unprecedented 76 unforced errors. It is improbable that Djokovic will be as erratic here so Millman's dream run is likely to come to an end.
The Serb's level has fluctuated in most of the matches he has played so far, and that could offer a set to Millman, but the two-time champion has to be favoured to reach the semi-finals.