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.
Nole beat Marin Cilic in five-set battle 6-1, 3-6, 6-7 (4), 6-2, 6-2 to reach his fifth Wimbledon semi-final in a row.
Novak advanced to the quarter-finals of the Championships with a 6-3, 6-4, 7-6 (5) victory over Jo-Wilfried Tsonga. He next faces Marin Cilic.
The 2011 titlist withstood a challenging third round encounter against Gilles Simon, as he beat the Frenchman 6-4, 6-2, 6-4 in two hours and 12 minutes.
No.1 seed spent 3 hours and 17 minutes in seeing off world no.38 Radek Stepanek 6-4, 6-3, 6-7 (5), 7-6 (5) in their second round encounter on Wednesday.