Wildcard Denis Istomin prevailed in five grinding sets after four hours and 48 minutes of play at Rod Laver Arena on Thursday.
Novak eased past Argentine Horacio Zeballos 6-3, 6-4 in 72 minutes on Wednesday to advance into the last eight in Doha.
The reigning Paris Masters champion beat world no.34 Gilles Muller 6-3, 6-4 and next faces no.14 seed Grigor Dimitrov (Thursday).
Nole began his title quest at the ATP Masters 1000 event with a comfortable 6-3, 6-3 victory over world no. 50 Fabio Fognini.
The top seed and defending champion will face Mikhail Youzhny (RUS) in the third round on Friday.
Nole defeated Gilles Muller 7-5, 7-6 (3) for a place in the third round of the Canada Masters on Wednesday.
Nole captured his 30th straight Grand Slam win beating Frenchman Adrian Mannarino 6-4, 6-3, 7-6 (5).
Novak recorded a 7-5, 6-3, 6-4 win over Steve Darcis in the second round action at Roland Garros on Thursday.
Nole opened his Internazionali BNL d’Italia campaign with a 7-5,7-5 win over 35-year-old French qualifier Stephane Robert (ATP #103).
World no.55 Jiri Vesely ended Novak’s Monte-Carlo Rolex Masters campaign with a 6-4, 2-6, 6-4 win in two hours and six minutes on Wednesday.