The 25-year-old 2010 world champion, winning here for the second successive year, came home clear on his Yamaha ahead of Italy's nine-time world champion Valentino Rossi on a Ducati, while Honda's Spanish rider Alvaro Bautista was third.
On an emotional day both Rossi and Bautista dedicated their finishes to the late Marco Simoncelli, who was killed in the Malaysian MotoGP last year and after whom the circuit here is now named.
Lorenzo had begun the day only 13 points ahead of compatriot Dani Pedrosa but the Honda rider was taken out of the race on the first lap by accident-prone Hector Barbera.
Pedrosa had a nightmare, having to start from the back of the grid because of brake problems on the warm-up lap after he qualified in pole.
Lorenzo leads Pedrosa by 38 points with five races remaining.
"It is bad luck for Honda but a great result for us. I am very happy to finally have the luck come down on our side," said Lorenzo.
Rossi, who joins Lorenzo next season at Yamaha, was delighted to have equalled his season best performance - though his previous second place came in the rain-affected French MotoGP.
"I think this second place is something special," said the 33-year-old.
"First because it is in Misano which is very close to my home town and secondly the circuit is in the name of Marco (Simoncelli) and I dedicate this runners-up position to him and his family."
Lorenzo had no problems at the start easing away while Rossi had a super start, surging into second, and Stefan Bradl also passed Cal Crutchlow who later in the lap was overtaken by team-mate Andrea Dovizioso.
Crutchlow's determination to regain the places he had lost on the first lap ended in disaster as with 23 laps remaining he slid off and was left clutching his knee.
Bradl began to close on Rossi with 15 laps remaining while Dovizios also took closer order but it was Bautista who was making the most progress with a succession of fastest lap times on his Honda.
Bautista passed Dovizioso into fourth with 11 laps to go and set off in pursuit of Bradl and Rossi with Lorenzo out on his own nearly six seconds clear.
Bautista's remorseless momentum saw him then get the better of Bradl with nine laps to the finish and five laps later both Dovizioso and American Yamaha rider Ben Spies overtook a weakening Bradl.
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