Marquez's eighth triumph at MotorLand came after an intense battle with Aprilia's polesitter Marco Bezzecchi, whom he overtook in spectacular fashion on lap six as they went side-by-side at over 300 kph.
KTM's Pedro Acosta finished second, extending his wait for a maiden MotoGP victory despite claiming his 14th podium finish, while Bezzecchi rounded out the top three and Alex Marquez finished fourth.
Having won Saturday's sprint, Marquez claimed maximum points over the weekend to move up to 237, leapfrogging Bezzecchi (232) to climb to second behind Aprilia's Martin (256), who finished fifth.
Bezzecchi had snatched pole position with a lap record, but Marquez pounced on turn one to win the sprint, with the Spaniard attempting the same move in the race, only to see the Aprilia rider retake the lead at the next turn.
"The key point was the first corner. I did it again, but I did a huge mistake today because I forgot the rear (ride-height) device and when I got from turn one to turn two, the rear device was activated and loaded again," Marquez said.
"I was super slow on that fast turn two and three; two riders overtook me. Then, it was more difficult, but from that point, I just built the pace."
Marquez had to go on the offensive to reel in Bezzecchi, setting fastest laps as he set his sights on the Aprilia in front of him while Acosta stayed glued to his rear wheel in third.
The reigning champion pounced on lap six, going alongside Bezzecchi on the back straight, riding mere inches apart and nearly making contact before overtaking the Aprilia.
"I heard his bike on turn 15 so I tried to cross the line, but when we were close, the slipstream was pushing each other very much, and it was strange," Bezzecchi said.
"Marc, with the experience that he has and the speed that he has, today he was unbeatable."
Acosta also took the opportunity to move up to second at the next turn to hunt down Marquez, with the home fans roaring in delight as the two Spaniards then battled for the lead.
But Marquez's consistency in setting fastest laps allowed him to put distance between him and Acosta, breaking the younger rider's resolve as the lead grew to over a second while Bezzecchi was nearly three seconds behind.
Riding the wave of another Aragon triumph, Marquez hopped off his bike on the victory lap and hitched a ride to the stand named after him, sinking to his knees amid the deafening acclaim of supporters dressed in Ducati red.
