Tykes' top-scorer O'Grady converted a penalty in first-half injury time at Oakwell before sealing the points with a close-range header minutes after the restart.
The success was Danny Wilson's first since he returned to manage the struggling South Yorkshire club six games ago and handed Blackpool an eighth defeat from nine Sky Bet Championship games.
Paul Ince's side were the first to threaten when Steve Davies' fourth minute header from Angel Martinez's cross was saved by Barnsley goalkeeper Luke Steele.
American winger Brek Shea, making his home debut following a loan switch from Stoke, went close at the other end in the 10th minute with a powerful left-footed drive from the right-hand edge of the box which ricocheted off team mate Peter Ramage and flew narrowly wide.
Matt Gilks then pulled off two close-range saves to prevent Tykes midfielder Jim O'Brien breaking the deadlock after 20 minutes. The Tangerines keeper reacted quickly to deny O'Brien's initial effort - an audacious backheel following O'Grady's right-wing centre - before catching the Scot's tame follow-up.
The visitors were denied an opener two minutes prior to the break when striker Davies tapped home a low ball across the box only to be flagged offside.
And it was Barnsley who went in ahead at half-time thanks to O'Grady. Tykes midfielder Stephen Dawson raced into the box before being upended by keeper Gilks and O'Grady calmly found the top right-hand corner from 12 yards with the last kick of the first-half to claim his eighth strike of the season.
O'Grady did not have to wait long for another opportunity and duly doubled his side's lead within three minutes of the restart. Midfielder O'Brien controlled Ryan McLaughlin's punt into the box before sending the ball across goal for O'Grady to head into the bottom left corner from close range.
Dale Jennings was denied his first Barnsley goal on the hour mark when the offside flag went up prior to his placed finish, before Tom Ince's penalty appeal was waved away at the other end after he tangled with full-back McLaughlin.
Blackpool midfielder Chris Basham tried to halve the deficit in the 73rd minute but his powerful goal-bound strike was bravely blocked by Tykes centre-half Ramage.
Basham saw another strike, this time from long range, repelled by Barnsley in the final minutes, while substitute Nathan Dyson fired woefully over as the Lancashire side failed to score for the fourth successive league game.