The Yamaha rider, who is hunting his third crown in grand prix racing's top division, sprinted into the first corner from pole position and was never headed.
Both Marquez and Honda team-mate Dani Pedrosa put Lorenzo under pressure under extreme pressure during the middle stages of the race, but with Lorenzo's bike better off the Motegi corners, he was able to hold them at bay.
After preserving his soft-compound tyres and brakes during that crucial phase of the race, Lorenzo was able to stretch away to his 30th career win - and his seventh of the season.
Lorenzo's victory cut his points deficit to Marquez - who finished second – to 13 points with 25 up for grabs at the Valencia finale.
Dani Pedrosa, who was also in title contention at the start of the race, was third and is now out of the championship hunt.
Alvaro Bautista and Stefan Bradl made it four Hondas in the top five positions, the Gresini rider overtaking LCR's German rider under acceleration out of the final corner at one-third distance.
Valentino Rossi sprinted up to second at the start, but ran wide at Turn 11 on the second lap, dropping behind Marquez and Pedrosa, dropping to fourth.
He then repeated the error at the same corner next time round, but this time made it all the way to the gravel and rejoined 11th. He recovered to sixth by the finish.
Cal Crutchlow was Tech 3 Yamaha's best finisher in seventh, the Briton recovering from a dismal qualifying that left him 11th on the grid. He overtook team-mate and countryman Bradley Smith around the midway point.
Nicky Hayden – who started third – beat Ducati team-mate Andrea Dovizioso to ninth spot.
Colin Edwards was the best CRT rider, the Forward Racing FTR-Kawasaki benefitting when Aleix Espargaro – who had run as high as fifth overall on the opening lap – crashed.