England, set 177 for victory, were bowled out for 155 at a chilly and rainswept Riverside.
Barbados-born Brathwaite, 29, had been West Indies' hero with the bat when they beat England in last year's World Twenty20 final, hitting four successive sixes off rival all- rounder Ben Stokes in a dramatic last over.
There was no re-match for Stokes, with England controversially resting the all-rounder for a fixture on his Durham home ground.
Instead paceman Brathwaite, in his only match of the tour -- he was not selected for the Test or one-day international legs -- took three wickets for 20 runs in 3.3 overs with the ball.
The first ball of England's reply saw Jason Roy caught at backward point by a diving Evin Lewis after he sliced a drive off Jerome Taylor.
Alex Hales was almost out for a golden duck as well but Rovman Powell dropped a tough diving chance following a firm clip off the pads.
Brathwaite, however, bowled Hales for 43 made off just 17 balls, including eight fours and a six.
Hales's exit was the start of a slump that saw England lose three wickets for four runs as 64 for one soon became 68 for four.
Brathwaite caught England Test skipper Joe Root (17) on the drive off Ashley Nurse.
And Nurse's fellow spinner Sunil Narine then had Twenty20 skipper Eoin Morgan out for just two when the dangerman reverse swept straight to Lewis at short third man.
Narine was named man-of-the-match after taking two for 15, with none of the West Indies side on show Saturday having featured in a preceding 2-1 Test series defeat by England.
Jos Buttler (30) helped Jonny Bairstow add 50 for the fifth wicket before he holed out off Kesrick Williams.
England badly needed someone to stay with Jonny Bairstow but David Willey charged at Narine and was comfortably stumped by wicket-keeper Chadwick Walton.
Brathwaite then had Bairstow (27) holing out in the deep.
England needed 26 off the last over and Brathwaite, fittingly, ended the match when he bowled Liam Plunkett.
Earlier, West Indies made 176 for nine.
Chris Gayle (40) and Lewis (51) got the tourists off to a flying start, putting on 77 for the first wicket after Morgan won the toss.
But fast bowler Plunkett (three for 27) and leg-spinner Adil Rashid, whose figures of three for 25 were his best at this level, kept West Indies to under 200.
The third over saw Gayle smashed left-arm paceman Willey for two successive sixes -- a pull followed by a powerful straight drive.
Lewis got into gear in the sixth over as he hit 16 runs in three balls off Tom Curran.
Gayle's 21-ball innings, featuring three fours and four sixes ended when, after guiding Plunkett to backward point, he was run out by as he ambled for a single.
The 37-year-old Gayle, in common with several senior West Indies players, had been involved in a bitter dispute with Caribbean cricket chiefs.
But July saw him return to West Indies duty in a Twenty20 international against India in Kingston.
That match saw fellow left-hander Lewis make a stunning 125 not out.
Lewis threatened another big score on Saturday while making fifty off 26 balls, including six fours and three sixes
The Trinidadian, however, was out soon afterwards when he drove Plunkett straight to Root at mid-off.
And four balls later, West Indies' 106 for two had become 115 for three when Marlon Samuels (10) mistimed a drive to Root at mid-on.
England and West Indies begin a five-match one-day international series in Manchester on Tuesday.
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