The 37-year-old Yamaha rider led every lap on the way to his 113th career victory, and record 87th in the top class. He had started on pole position and also set the fastest lap.
Team mate and reigning world champion Jorge Lorenzo, who passed Rossi for a matter of seconds on lap two before being swiftly put back in his place, finished second for his 100th MotoGP podium.
Championship leader and fellow Spaniard Marc Marquez, who had a headline-grabbing spat with Rossi at the end of last season when the Italian accused him of helping Lorenzo, was third for Honda.
After four of the season's 18 races, and the first in Europe, Marquez has 82 points and Lorenzo 65.
Rossi, whose first win was almost 20 years ago in the 125cc class in 1996, is third with 58.
"This was the perfect weekend," said the Italian, who will have a new team mate next season with Lorenzo leaving for Ducati, after finishing 2.3 seconds clear.
"The bike in the race was fantastic...I had a good pace, a good start, I feel good with the bike from the beginning so I can push. It was a special taste, a win like this."
Rossi had not won since last August's British Grand Prix at a wet Silverstone, but Jerez has been good to him in the past and Sunday was his seventh top flight victory there in 17 starts.
Lorenzo felt he would have won but for tyre problems that forced him to ease off.
"The pace from the beginning was not very fast, said the man who set a lap record on his way to victory in Jerez last year. "Rossi was a little bit faster than me at the beginning of the race but in the middle I could keep the distance.
"When I was catching him, suddenly the centre of the tyre on the straight when I put third, fourth, fifth and sixth gears was spinning like I had wet tyres," he added.
Marquez had similar problems and said it had been simple damage limitation.
"I tried and pushed behind Lorenzo but I nearly crashed one, two, three times," he said. "Then I said 'OK, 16 points for the championship'. These two guys today were faster."
(Writing by Alan Baldwin in London, editing by Ian Chadband/Toby Davis)
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