Djokovic earned his 300th ATP World Tour Masters 1000 victory, beating no.31 seed Juan Martin del Potro 7-5, 4-6, 6-1.
The defending champion goes on to face no.31 seed Juan Martin del Potro for a place in the ATP Masters 1000 event last 16.
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.