After India's thrilling run chase at the Oval on Wednesday had levelled the series at 3-3, Saturday's clash fizzled into anti-climax after India were bowled out for 187.
England lost openers Luke Wright and Matthew Prior for ducks to raise hopes among the thousands of India fans in a sell-out crowd but unbeaten scores of 71 from Kevin Pietersen and 64 from captain Paul Collingwood guided them home with 13 overs to spare.
Andrew Flintoff, who returned to the England side after passing a fitness test on his ankle, and Dimitri Mascarenhas both took three wickets in the India innings after Rahul Dravid had won the toss and elected to bat.
Only Mahrendra Singh Dhoni's belligerent 50 salvaged some respectability for India who never recovered from a ragged start.
Opener Sourav Ganguly got away with several rash strokes in his scratchy 15 before he edged a pinpoint delivery from paceman James Anderson to the safe hands of Flintoff at second slip.
It was a disappointing day for India batsman Sachin Tendulkar who was making possibly his last appearance at Lord's. He was the victim of a questionable umpiring decision by Aleem Dar, adjudged to have nicked a Flintoff delivery behind to Prior having scored 30.
Dhoni blazed away with a six and four boundaries as India looked to at least give their bowlers something to defend.
His half century came up in 69 balls but he ran out of partners as Powar was run out, Chawla was stumped by Prior to give Mascarenhas his third wicket and Zaheer Khan was bowled by Monty Panesar.
Dhoni was the last man to fall when he tried to slog a slower delivery from Flintoff and went to an excellent diving catch on the long-off boundary from Anderson.
Despite chasing a modest target, England began in reckless fashion and Wright was caught and bowled in the second over when he unwisely tried to hook an RP Singh bouncer.
Prior followed him back to the pavillion when he nibbled an outswinger from Singh to wicketkeeper Dhoni in the same over.
Ian Bell, England's most consistent batsman throughout the series, restored order with Pietersen as they shared a partnership of 63 before he was run out for 39.
Pietersen played well within himself as he and Collingwood broke India's resolve, one straight six off impressive spinner Piyush Chawla a rare display of aggression.
They put on 114 in 20 overs with Pietersen hitting the winning runs over the top off Ramesh Powar.