Djokovic overcame a wobble in the first round to defeat Marton Fucsovics in the intense New York heat. The Serb struggled physically at times and lost the second set with a potential upset appearing to be on the cards, but he recovered well and ultimately eased towards the finish line as the heat then took its toll on his opponent.
The former winner has been handed a night match this time around and he will welcome the cooler conditions as he seeks to continue his excellent second half of the season.
Djokovic made light work of Sandgren in their only previous meeting - a straight sets win on his way to the Wimbldeon title in July.
Despite a run of poor form in the build-up to the US Open, Sandgren recorded a straight-sets victory in the first round by dismissing the higher-ranked Viktor Troicki with relative ease.
The American is seeking to recapture the form that took him to the quarter-finals at the Australian Open earlier this year, by far his best ever performance at a major.
The 27-year-old barely laid a glove on Djokovic during their first round meeting at Wimbledon so he will need to bring something else to the table if he is to compete with the two-time former winner.
There were some nervy moments during Djokovic's four-set victory over Fucsovics a couple of days ago but that was as much to do with the punishing weather conditions as anything else. In this night match, the Serb should have no such trouble and it is likely to be a one-sided affair, as it was when the pair met at Wimbledon in early July.
Expect Djokovic to dominate from the back of the court and ease to a straight sets win.