Pietersen, who missed the visitors' last ODI because of a fractured left thumb, returned in style with a match-winning knock that came off 39 balls as England chased down India's modest 121-run target with eight balls to spare.
After being dropped on one by Suresh Raina, Pietersen hit five boundaries and three sixes en route his quickfire innings as the reigning T20 champions proved their supremacy in the shortest format of the game.
Samit Patel was the second-best run-maker for England with a 25-ball 21, while Ravi Bopara remained unbeaten on 14.
Earlier, India produced an ordinary batting performance to be restricted to 120 for nine.
India captain Mahendra Singh Dhoni's decision to bat first at a slowish Eden Gardens pitch backfired as barring Suresh Raina (39) and the skipper (21) himself, no other batsmen could post a challenge before the determined English attack.
Virat Kolhi and Manoj Tiwary made identical 15 and towards the end R Ashwin (17) played a short-little cameo to help the home team's cause.
Right-arm pacer Steven Finn, who impressed in the just-concluded ODI series, was the pick of the English bowlers with figures of three for 22, while Tim Bresnan (2/19) and part-timer Ravi Bopara (2/16) gave him the perfect support from the other end.
England, however, did not have the best of the starts while chasing against an all-spin Indian attack.
Ashwin and Pathan managed to hold the England openers but it was left-arm spinner Jadeja who gave the first breakthrough removing Kieswetter for 12 to give some ray of hope to the Indians.
England could have been further trouble if not for otherwise an agile Raina, who dropped Pietersen in the next over with the star batsman on one.
Three Indian fielders chased for Pietersen's top-edge that came from Ashwin's bowling and in the end Raina went for it, only to put it down, in what appeared to be the turning point of the match.
Pathan dismissed the other opener Alex Hales (11) but Pietersen grew in stature, unperturbed of what's happening around him.
After a cautious start, Pietersen opened up with some good blows against Pathan as he stitched a decisive third wicket 60-run partnership with Samit Patel.
The duo completed 50 runs together from 36 balls as the target looked within reach.
Pietersen completed his half-century from 34 balls with three sixes and five boundaries before he was adjudged leg before wicket to Raina, 15 runs short of the target.
But from there on victory was just a formality as Bopara and Jonny Bairstow (2 not out) ensured that there was no further damage and gave England its first win in the tour.
Earlier, India witnessed a disastrous start losing both the openers cheaply. Having waited in the sidelines for more than three years,
Robin Uthappa's comeback match turned out to be a nightmare as, sent in as an opener, he could manage only one.
Uthappa's opening partner, Ajinkya Rahane , who shone with the bat in England as well as in the ODI series at home, too did not last long and fell for a duck.
Uthappa was caught unaware by a rising Bresnan delivery, while Mumbai youngster Rahane disappointed with a poor shot selection against Finn as both were dismissed caught behind.
In need of a partnership with the scorecard reading five for two, in-form Kohli looked in fine nick as he began the repair work with vice-captain Raina.
Kohli, who was the Indian top-scorer in the ODI series against England, looked in an ominous mood before Bresnan cut short his innings, brilliantly caught by a running Hales.
But Raina in debutant Tiwary's company then started to resurrect the Indian innings with a 40-run fourth wicket stand before the former was cleaned up by left-arm spinner Patel.
Finn then removed Raina and scalped Jadeja in two successive leave tottering at 74 for six.
India once again banked on Dhoni to marshal the sinking ship, but the captain became a mute spectator when Bopara took two wickets in the form of Pathan (10) and Praveen to add to the home team's misery.
At 91 for eight, India looked in danger of being bowled inside 100, but R Ashwin (17) played a nice cameo in Dhoni's company to take the score to the 120-mark.
