Yamaha rider Lorenzo moved methodically to the front after starting fourth on the grid, only suffering one late wobble while clear at the front.
It was the Spaniard's fourth win in six races this season, and he has not finished outside the top two yet.
Casey Stoner made the early running, but faded due to chatter issues and narrowly held off Honda team-mate Dani Pedrosa to finish second.
But the home crowd's real hero was Cal Crutchlow, who finished a brilliant sixth after starting from the back of the grid.
Crutchlow broke his left ankle crashing in practice and took no part in qualifying, but defied the pain with a magnificent performance.
Cructhlow told the BBC he was: "A little bit emotional and drained," and said he would have been on the podium had he not started from the back.
Pole-sitter Alvaro Bautista had to settle for fourth, while Lorenzo's Yamaha team-mate Ben Spies was fifth.
Valentino Rossi suffered yet another difficult afternoon on his Ducati. The Italian was never on the pace and finished ninth, two places behind his team-mate Nicky Hayden.
James Ellison claimed a creditable points finish on the Paul Bird Motosport CRT machine.