Quartararo got the best start and from pole, with Rossi also getting away well from P4, but drama unfolded behind as fifth place Miguel Oliveira (Red Bull KTM Tech3) crashed in a Turn 1 melee that also then involved Brad Binder (Red Bull KTM Factory Racing) and Bradley Smith (Aprilia Racing Team Gresini).
The Portuguese rider was down and out of the race, with Binder running off circuit and dropping to the back and Smith's race compromised too.
There was a three-way Yamaha scrap at the front though, and it was Quartararo leading Vinales and Rossi, who had a slight gap to the two Pramac Racing riders of the quick starting Jack Miller and Francesco Bagnaia just behind.
Quartararo was getting down to business quickly though with the hammer well and truly down, and Vinales went wide at the final corner trying to pounce.
Quartararo's lead on Lap 4 was up to 1.5sec, and Vinales could not find a way through on Rossi to try and give chase. The Pramac Racing duo were also breathing down the YZR-M1 rider's neck as the number 20 Petronas Yamaha SRT started to clear off into the distance, and Rossi could not do anything about Quartararo's pace either. By Lap 6 the Frenchman's lead was nearly three seconds.
Race of attrition
With 10 laps down that lead was looking unassailable, with Bagnaia making progress to get through on Miller and Vinales, as the Italian locked his radar onto the boss' rear wheel.
The race in Jerez was quickly starting to become a race of attrition in the blistering Andalusian heat, however - with some parts of the track over 63 degrees.
Vinales was clambering all over the back of the number 46, but Rossi was a demon on the brakes and it was really looking like Vinales just would not be able to find a way through.
Then though, after not having put a wheel wrong the whole race, Rossi was slightly wide at Turn 9 - and Top Gun pounced as Vinales was up to second.
At the front though it was all about one man as Quartararo made no mistakes in the brutal conditions to take his second consecutive victory, cementing his lead in the Championship over second-placed Vinales.
Rossi's return to the rostrum was more than welcomed for the 41-year-old, the number 46 putting in a mesmerising ride to notch up his 199th MotoGP podium, and his 235th across all classes.