The Spaniard led throughout on his factory Yamaha at Misano to end Stoner's three-race winning run, with compatriot Dani Pedrosa second as Stoner was forced to settle for the final podium spot.
From second on the grid, Lorenzo stole ahead of his title rival into the first corner and never relinquished it thereafter, with Pedrosa steadily reeling in the Australian -his Repsol Honda team-mate - and claiming second spot with seven laps remaining.
Stoner believed fatigue was responsible for his poor showing on the day.
"I was pretty comfortable behind Jorge, I didn't feel the need to push and then the tiredness suddenly hit me," he said.
"It was hard to find the braking points and change direction on the bike.
"There was nothing wrong with the tyres, nothing wrong with the bike, the team did a great job and gave me a fantastic package, I'm just worn out."
Lorenzo was surprised by the lack of a challenge, and told Autosport.com: "I really expected a very hard fight with Casey, but fortunately for me Casey lost a little bit of pace in the middle of the race and I could win a second victory in Italy. This is very important."
Third placed Pedrosa added: "The second part of the race was good, Jorge had a perfect race today, but I was able improve my times lap by lap and catch Casey. I overtook him and maintained my rhythm to the finish with another second place in two weeks, which it's not so bad."
Marco Simoncelli was fourth for San Carlo Honda Gresini, the Italian having slipped from fifth to seventh at the start but battled his way to pip fellow countryman Andrea Dovizioso (Repsol Honda) on the final lap.
Lorenzo's team-mate Ben Spies and Ducati's local hero Valentino Rossi followed, with the top 10 completed by Spaniards Alvaro Bautista (Rizla Suzuki) and Hector Barbera (Mapfre Aspar) and Great Britain's Cal Crutchlow on the Monster Yamaha.
There were 15 finishers in total, with Nicky Hayden crashing out on lap three and tyre problems ending Loris Capirossi's challenge on lap nine.
The result leaves Lorenzo 25 points behind Stoner, who remains the championship leader with 259. Dovizioso is third on 185, with Pedrosa fourth on 150.