Vettel passed pole-sitter and teammate Mark Webber in the first corner and held the lead throughout, capping off a 1-2finish for Red Bull. Nico Rosberg finished third for Mercedes as forecast rain stayed away from the 3.44-mile Sepang circuit.
Despite getting away well Webber lost pole at the first corners, and Vettel - who retired from the lead in Melbourne last weekend - took a comfortable victory.
Nico Rosberg secured a maiden podium for Mercedes, who lost seven-times champion Michael Schumacher with a wheel nut issue after only 11 laps.
Briton Lewis Hamilton shot up the inside ahead of the first corner, making up seven places -including that of world champion team-mate Jenson Button- for 13th with Felipe Massa following Hamilton all the way.
He finished the race sixth ahead of the Brazilian, with Button eighth. Robert Kubica took fourth for Renault ahead of Adrian Sutil of Force India.
Jaime Alguersuari and Nico Hulkenberg rounded out the points positions.
Once Vettel's electric start allowed him to sneak through in the turn one-turn two complex at Sepang, he dropped into second only once - over the extra couple of laps for which Webber stayed out during the pitstops.
The two RB6s quickly left the following Rosberg and Kubica behind and were alone for practically the entire race.
The only issue for them arose when the right-front wheelgun during Webber's stop - on lap 24 - would not come away immediately, costing him a couple of seconds.
That saw Hamilton, who had quickly made up another three places and saw the field ahead of him disappear into the pits, spend some time in P2. He stayed out longer than everyone other than Fernando Alonso, who retired with only two laps remaining while trying to get past Button.
As Hamilton re-emerged from the pits on lap 31 the McLarenpair were wheel to wheel, with the 2008 world champion just keeping the racing line ahead of the reigning champ.
Button, who had taken 14th from Alonso in the early laps after making up two spots himself off the line, pitted as early as lap 10 and suffered in the latter stages with well-worn tyres.
With 12 laps remaining he had to relinquish eighth to Massa, who immediately set about catching Hamilton. The Briton had been all over Sutil, but dropped back in the last laps to concentrate on fending off his title rival from two years ago.
Alonso ran wide after passing Button and smoke immediately began to pour from the back of the F10, signalling the end of his race.
Heikki Kovalainen was also unclassified while Vitaly Petrov, Vitantonio Liuzzi, Timo Glock and Kamui Kobayashi all saw their races ended by mechanical faults - while Kobayashi's team-mate Pedro de la Rosa never made it to the start line, his Sauber coming to a stop at turn three as the drivers made their way around the circuit to the grid.
Sebastien Buemi fought for 11th in the Toro Rosso, ahead of Williams' Rubens Barrichello, Alonso, Lucas Di Grassi of Virgin, Hispania pair Karun Chandhok and Bruno Senna and the ailing Lotus of Jarno Trulli.Next up is the Chinese Grand Prix on April 18.