No.10 seed Kei Nishikori upset the top seed in four sets – 6-4, 1-6, 7-6 (4), 6-3, becoming the first Asian man to reach a Grand Slam singles final.
Novak reached his eighth consecutive US Open semi-finals with a 7-6 (1), 6-7 (1), 6-2, 6-4 win over Andy Murray on Wednesday night.
2011 titlist powered into the last eight at Flushing Meadows on Monday, with a 6-1, 7-5, 6-4 victory over no.22 seed Philipp Kohlschreiber.
2011 champion advanced to the fourth round in New York on Saturday as he dismissed Sam Querrey 6-3, 6-2, 6-2.
Nole improved his record to 6-1 against Paul-Henri Mathieu, beating the Frenchman 6-1, 6-3, 6-0 for a place in the US Open third round.
The top seed closed out a routine 6-1, 6-2, 6-4 win over world no.79 Diego Schwartzman to advance into the second round of the 2014 US Open on Monday night.
Top seed and 2011 champion will open campaign in his 10th US Open appearance against world no.79 Diego Schwartzman of Argentina.
Novak starts his US Open Series campaign at the Rogers Cup, taking place in Toronto, Canada, from August 4-10.
Novak will play for his second Wimbledon title on Sunday (15.00 CET) when he meets no.4 seed Roger Federer.
Novak beat no.11 seed Grigor Dimitrov 6-4, 3-6, 7-6(2), 7-6(7) in three hours, two mins on Friday to reach his third final at the All England Club.