Home hero Andrea Dovizioso stole the lead from Lorenzo into turn one, and the Spaniard was later briefly bumped down a further position by arch-rival hector Barbera.
But the #1 soon regrouped and began a thrilling dice with Dovizioso, which ended prematurely when Dovi's Honda ground to a halt with mechanical problems.
Lorenzo was unchallenged thereafter, with KTM team-mates Hiroshi Aoyama and Mika Kallio overcoming Barbera to battle for the runner-up position. That battle also ended early, in spectacular fashion, when Kallio suffered a huge highside.
That allowed Barbera to regain the final podium position, but only after holding off class rookie Thomas Luthi and home star Alex de Angelis at the line.
Lorenzo, set to join Italian legend Valentino Rossi in the factory Yamaha team next year, celebrated his win by dressing as a Roman Gladiator - complete with helmet, body armour and sword!
The Fortuna Aprilia rider is now 54 points ahead of Dovizioso in the title chase, with five rounds remaining.
Race results – Misano:
1. Lorenzo (Aprilia)
2. H. Aoyama (KTM) +3.578secs
3. Barbera (Aprilia) +7.041secs
4. Luthi (Aprilia) +7.213secs
5. de Angelis (Aprilia) +7.664secs
6. S. Aoyama (Honda) +36.234secs
7. Locatelli (Gilera) +36.918secs
8. Bautista (Aprilia) +36.936secs
9. Takahashi (Honda) +37.142secs
15. Laverty (Honda) +1min 9.950secs
Linfoot (Aprilia) DNF