The world champion was 0.421 seconds faster than Red Bull's Daniil Kvyat in the brief period of dry running.
A late shower prevented Ferrari's Sebastian Vettel completing a lap that would have offered comparison.
The second Red Bull of Daniel Ricciardo was third but ended the session with an off at Turn 13 in the wet conditions.
The Australian, who ran wide on the exit of the most demanding section on the track with no major ill effects, was 1.15secs off Hamilton's quickest lap, but time comparisons were virtually meaningless in the circumstances.
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Despite the tricky conditions and teams' reluctance to do more than a handful of laps on a track that holds plenty of dangers, 20 of the 22 drivers set a time.
Only Vettel and Toro Rosso's Carlos Sainz, whose car had technical problems, failed to record a timed lap.
Ferrari's Kimi Raikkonen, Toro Rosso's Max Verstappen and Manor's Indonesian novice Rio Haryanto all had incidents.
Raikkonen and Verstappen both spun, at Turn 13 and Turn Six respectively, while Haryanto ran wide into the gravel, also at Turn Six.
Hamilton's team-mate Nico Rosberg was only sixth fastest, behind Force India's Nico Hulkenberg and Verstappen, and two seconds off Hamilton's pace.
The McLarens of Fernando Alonso and Jenson Button were next, with Force India's Sergio Perez and Renault's Kevin Magnussen completing the top 10.
The second session starts at 05:30 GMT, with the unpredictable conditions expected to continue through the day at Melbourne's Albert Park.
Australian GP first practice results
Australian GP coverage details
Lewis Hamilton set the pace in the first practice session of the new season, held in intermittent rain at the Australian Grand Prix.