As speculation over his future continued to dominate paddock conversation, Hamilton set the pace with a 1m25.290s lap.
That time was achieved on the softer of this weekend's Pirelli tyres, as was Spa winner Jenson Button's 1m25.328s lap in second place in the sister McLaren.
The Woking squad's move to the front was at the expense of home favourite Ferrari, which had led the way through the middle part of the session.
But despite the speed that saw him on top for a long spell with a 1m25.348s on hard tyres, championship leader Fernando Alonso had a number of problems.
First a brake issue required attention, then a gearbox issue curtailed his session.
Alonso's time still held up for third, just 0.058 seconds off the pace.
His team-mate Felipe Massa was next up. The Brazilian's only glitch was a vent flying off the top of his helmet at speed.
Nico Rosberg completed the top five for Mercedes. His morning practice pace-setting team-mate Michael Schumacher suffered DRS gremlins throughout the afternoon, and was back in 10th.
Kimi Raikkonen was fastest for a while early on and ended up sixth in the lead Lotus.
His one-off team-mate Jerome d'Ambrosio - standing in for the banned Romain Grosjean - was 0.6s slower in 12th.
Force India continued its strong Spa form to take seventh and eighth, Nico Hulkenberg ahead of Paul di Resta. Sauber's Sergio Perez was next up.
It was a quiet session for champion team Red Bull. Mark Webber and Sebastian Vettel were back in 11th and 13th.