The McLaren driver showed his one-lap speed on hard and medium compound tyres alike, with his best of 1:38.172 meaning he ended the session more than three-tenths of a second ahead of Michael Schumacher's Mercedes.
Australian Grand Prix winner Jenson Button was just two-thousandths of a second behind the German in third place, while Nico Rosberg took fourth.
Both Toro Rossos finished in the top 10, with Daniel Ricciardo fifth and Jean-Eric Vergne eighth, as did the Red Bull duo of Mark Webber (7th) and defending champion Sebastian Vettel (10th).
Fernando Alonso improved from his struggles in the morning session to lift his Ferrari up to sixth place, while Romain Grosjean ended the day in ninth.
There was plenty of action throughout the session, with rain threatening the Sepang circuit and forcing the teams out early, but the inclement weather in the area managed to miss the track.
Hamilton looked comfortably quicker than his rivals on the shorter stints, but had a couple of wobbles on the medium tyres when he simulated his first run of the race on his qualifying set-up, running wide and locking his tyres.
He was not alone, with tyre wear set to be a factor in the humid conditions.
The best times were set in the first hour of the session, with the latter part of the practice giving way to 'race' runs over longer stretches.
Any pace advantage McLaren enjoyed appeared to be gone over those longer runs, with Red Bull and even Alonso's Ferrari posting comparable sequences of times.
But having dominated qualifying in Melbourne, the McLaren duo look well-placed to hit the front of the grid again in Malaysia.