At tea, on the first day, England were 222 for two with Vaughan, who'd won the toss on his Yorkshire home ground, 92 not out and Kevin Pietersen unbeaten on 53.
The duo had so far put on 131 for the third wicket although Pietersen had a huge slick of luck when stumped off a no-ball on 20.
This was Vaughan's first Test in 18 months after he'd been sidelined with a career-threatening knee injury and a hamstring problem before a broken finger sustained while batting against Hampshire three weeks ago kept him out of the drawn series opener at Lord's.
Vaughan, 32, playing his first Test since appearing against Pakistan at Lahore in December 2005, had yet to give a chance.
England 91 for two at lunch, put resumed with Vaughan 25 not out and Pietersen yet to face.
Vaughan turned Corey Collymore for four before Pietersen's first scoring shot produced a boundary when he leg-glanced medium-pacer Dwayne Bravo.
He then confidently cover-drove, one of his signature shots, Bravo for four.
Then a misfield by opposing captain Ramnaresh Sarwan allowed Vaughan to complete a 94 ball fifty with seven fours.
Pietersen made sure runs came from both ends by disdainfully driving Collymore straight down the ground
He then had a break when Chris Gayle had him stumped with his second ball back by Denesh Ramdin, the batsman yards out, only for umpire Asad Rauf to call no-ball with England 142 for two.
Vaughan then played one of the shots of the match when he cover-drove Powell off the backfoot. And when the paceman overpitched Vaughan dismissively off-drove him for another four.
England's third wicket pair raced to a hundred partnership in 121 balls on a good pitch against an attack where only Gayle provided some variety.
Pietersen's sixth four, off Jerome Taylor, saw him to a 67-ball fifty.
Vaughan earlier put on 53 for the second wicket with Alastair Cook following the loss of Andrew Strauss.
But left-hander Cook - one of England's five centurions at Lord's - was out for 42 to the last ball before lunch, lbw to Gayle.
Strauss, who'd twice cut Powell for four, fell when he edged an attempted cut off the bowler to Ramdin for 15.
Vaughan got off the mark when he turned Powell through square leg and played the shot of the morning when he off-drove Taylor for four.
England's other change from Lord's saw Ryan Sidebottom, six years after playing his one and only previous Test, recalled in place of injured quick Matthew Hoggard.
West Indies suffered a blow here Friday when Shivnarine Chanderpaul, their senior batsman who top scored with 74 in the tourists' first innings at Lord's, was ruled out with tendonitis in his right knee.