The triple world champion, also hoping to become the first since the late Argentine Juan Manuel Fangio in the 1950s to win three years in a row at Monza, lapped the fastest circuit on the calendar in one minute 22.008 seconds.
That time, set on supersoft tyres, was more than a second quicker than the Briton's 2015 pole position time.
Team mate and title rival Nico Rosberg was second quickest, 0.393 slower.
Hamilton, who also set the pace in Friday practice, leads Rosberg by nine points with eight races remaining. Only two other drivers -- Michael Schumacher and Alain Prost -- have ever won 50 grands prix.
Monza is the last round of the European season and, with the sun beating down on the Ferrari faithful who festooned banners from the main grandstand, dominant champions Mercedes again look to leave their rivals trailing.
They have led every practice session one-two and can expect to sweep the front row in later qualifying.
Ferrari were best of the rest at their home circuit, four times champion Sebastian Vettel nearly a second off Hamilton's pace while Kimi Raikkonen was fourth and 1.141 slower than the Briton.
The top eight went in team pairs, with Williams duo Valtteri Bottas and Felipe Massa fifth and sixth and Red Bull's Daniel Ricciardo and Max Verstappen seventh and eighth.
Frenchman Romain Grosjean parked up in his Haas early in the session, triggering a virtual safety car, while Verstappen was caught seemingly unawares by Rosberg who had to slow at the second chicane.
"What on earth was that," exclaimed the German, who waved his hand at the Dutchman as he went past, over the team radio.
Verstappen's aggressive driving at the previous race in Belgium, and clash with both Ferrari drivers at the start, has been a big talking point at Monza although an expected showdown in the Friday drivers' briefing failed to materialise.
(Reporting by Alan Baldwin, editing by Amlan Chakraborty)
