Wildcard Denis Istomin prevailed in five grinding sets after four hours and 48 minutes of play at Rod Laver Arena on Thursday.
The defending champion passed a tough first-round assignment with a 6-1, 7-6, 6-2 victory over Spaniard Fernando Verdasco (ATP #40).
Second seed and six-time defending champion will open campaign in his 13th Australian Open appearance against world no.40 Fernando Verdasco.
Novak maintained his winning start to 2017 season with a hard-fought 4-6, 7-6 (7), 6-3 victory over Fernando Verdasco on Friday.
The second seed advanced to the last four with a 6-3, 6-3 victory over qualifier Radek Stepanek. He will next face Fernando Verdasco.
Novak eased past Argentine Horacio Zeballos 6-3, 6-4 in 72 minutes on Wednesday to advance into the last eight in Doha.
The defending champion overcame a slow opening to beat German Jan-Lennard Struff 7-6 (1), 6-3 in one hour and 27 minutes.
The defending champion kept up the pressure in the race for the year-end no.1 ranking with a convincing 6-1, 6-2 win over Belgian David Goffin on Thursday.
Novak has suffered quarter-final exit at the BNP Paribas Masters on Friday after he fell to no.9 seed Marin Cilic 4-6, 6-7 (2).
The reigning Paris Masters champion beat world no.34 Gilles Muller 6-3, 6-4 and next faces no.14 seed Grigor Dimitrov (Thursday).