The Seasiders scored twice in three minutes midway through the first half of the semi-final first leg.
And with Simms adding his second on the break late on, they are now in a seemingly unassailable position with the second leg to come at Bloomfield Road on Friday.
The early quickfire double knocked the stuffing out of the U's.
Karl Robinson's team had not recovered from that blow when they found themselves two down after 26 minutes.
Simms cut in from the right and flicked the ball over Rob Atkinson before firing home left-footed, the shot deflecting off Elliott Moore to leave goalkeeper Jack Stevens helpless.
Simms was clinical again in the 74th minute with his 10th goal in 23 games as the visitors counter-attacked at pace from their own half.
Jerry Yates and Simms combined with great understanding and the latter finished by slotting past Stevens.
The U's, who had qualified for the play-offs with a run of seven wins in their last nine games, were on the front foot from the start, encouraged by 3,200 socially-distanced fans back in the Kassam Stadium for the first time in months.
Mark Sykes was brought down just outside the area after a forceful run through the middle, the foul earning James Husband a yellow card, but Blackpool's wall stood firm to block Elliot Lee's low free-kick.
But the visitors then took charge to go into the half-time break 2-0 up and in buoyant mood.
Henry had a golden opportunity to pull one back just after the hour mark, only to sky his shot from Barker's cross high over the bar.
However, Blackpool impressively protected what they had, getting men behind the ball and stretching their opponents with devastating effect on the transition to make it a memorable night for Neil Critchley's men.