The reigning world champion delivered a 1m39.701s lap to topple erstwhile leader Dani Pedrosa by three thousandths of a second.
Lorenzo's team-mate Valentino Rossi was third fastest while Austin victor Marc Marquez was fifth, three quarters of a second back.
Pedrosa led the early running and was straight into lap-record territory, his first real effort a 1m39.855s, heading Lorenzo and Briton Cal Crutchlow.
Crutchlow again proved the quickest of the satellite bikes, finishing fourth fastest after running second for much of the session.
Pedrosa improved with just under 20 minutes of the session to run, his 1m39.704s good enough to help him top until Lorenzo's late flier dethroned him.
Karel Abraham rode 16 laps as he bids to race just two weeks after breaking his collarbone in qualifying at Austin.
He was 22nd quickest in practice with a best lap of 1m43.334s.