The Nottinghamshire opener made the highest Twenty20 international score by an English batsman on his home ground as Stuart Broad's side successfully chased 173 with two balls to spare.
Hales fell agonisingly short of the seventh century in Twenty20 international cricket when he was yorked by Ravi Rampaul in the penultimate over but Eoin Morgan hit the winning runs off the first ball he faced.
Hales shared a 159-run partnership with Ravi Bopara, who made 59 off 44 balls before holing out in the final over, as England completed a hat-trick of victories over the men from the Caribbean with this victory in the only T20 following 2-0 series wins in the Tests and one-day internationals.
Dwayne Smith anchored the West Indies innings with 70 off 54 balls including five sixes and Dwayne Bravo (54 off 36 balls) and Kieron Pollard (23 off 13) provided a strong finish with 63 from the last four overs but they paid for a slow start.
Hales hit four sixes and six boundaries from 68 balls in England's total of 173 for three from 19.4 overs.
England lost Craig Kieswetter early on for three making way for Ravi Bopara, who set about establishing a partnership with Hales.
Some timely boundaries from Bopara and a steady, assured knock from Hales kept England on course, with both batsmen turning up the run rate.
With just seven balls remaining, Hales was clean bowled and Bopara then scooped a ball straight to Fidel Edwards for an easy catch at long-off and was out for 59.
But with two runs needed off three balls, it was left to Morgan to hit the winning runs, helped by a Bravo misfield.
After England lost the toss and were asked to bowl their immediate hopes of victory were significantly boosted with the early dismissal of danger man Chris Gayle for two.
A Steven Finn short ball tempted Gayle, playing his first Twenty20 international in two years, to swipe at a ball he could only top edge high to Jonny Bairstow who held on well on the fine leg rope.
When Broad removed Lendl Simmons, also caught by Bairstow, with his first delivery, the tourists had been restricted to 29 for two after the initial six-over powerplay. England's early advantage was strengthened when Graeme Swann had Marlon Samuels caught behind by wicketkeeper Craig Kieswetter.
It was opener Smith who took up the lead role though, lofting both Swann and Samit Patel straight over the ropes, before his third six brought up his half-century from 46 balls. Broad was celebrating his 26th birthday by captaining his country on his home ground, but Smith was intent on crashing his party and he hammered another six over the bowler's head.
With partner Bravo content to feed Smith the strike he continued the slightly-delayed acceleration, back-cutting Patel for four as West Indies reached 100 off 91 balls. The opener pulled Finn for his fifth sixth but was out next ball when the England quick claimed his second important scalp when he cleverly fired a wide delivery that Smith chased only to edge behind.
That brought the big-hitting Pollard to the crease and he soon swiped Patel for a straight six before Bravo cleared the ropes from consecutive balls off Jade Dernbach as they gave West Indies hope of a first win over England on this tour.
Kevin Pietersen's premature retirement from limited overs cricket earlier this summer has left England relying on a talented if young batting line-up ahead of their World Twenty20 title defence later this year and Hales almost certainly booked his place on the plane to Sri Lanka with his match-winning knock.