The win ended a long drought for the three-times MotoGP champion, who has struggled since joining the factory outfit at the start of 2017 and whose last victory was for Yamaha in Valencia at the end of 2016.
Italian team mate Andrea Dovizioso was second, with compatriot Valentino Rossi third for Yamaha, making the 39-year-old great the first rider to score more than 5,000 points in the top category.
"Finally nobody could catch me... to win here with a Ducati is like a dream," said Lorenzo.
Rossi, who started on pole position, moved up to second place overall and is now 23 points adrift of Marquez who has 95 points from six races. Rossi is on 72.
Lorenzo led into the first corner, after lining up second on the grid, and stayed in front.
Marquez took second at the start of lap three but lost control two laps later, sliding into the gravel before remounting. He finished 16th of 17 still running.
Dovizioso passed Rossi on lap seven, with the Yamaha rider coming back strongly in the closing laps and finishing just 0.259 behind.
Lorenzo's future at Ducati has been called into question, with a parting of the ways looking likely at the end of the year, but the Spaniard said he had just needed to feel more at ease on the bike.
"A lot of people said that my method was not right," said Lorenzo after wild celebrations at the finish. "I said that I just needed to feel more comfortable...
"Finally when the team gave me a new fuel tank that I feel more comfortable (with), I could give a more constant pace."
Dovizioso, last year's winner at the scenic track north of Florence and now fourth overall with a 29-point gap to Marquez, said he and Rossi had both made the wrong front tyre choice.
"I saw Valentino lose the front three times in front of me," he said. "I couldn't push from the first lap. I think we did the wrong decision, we couldn't stay with Jorge. He did a really perfect race."
Rossi, the man most of the crowd had come to cheer, said he was just happy to be back on the podium.
(Reporting by Alan Baldwin in London, editing by Clare Fallon)
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