Ireland opened up a 22-0 lead after just over 30 minutes, taking full advantage of England's sloppy defending as Jamison Gibson-Park, impressive winger Rob Baloucoune and early replacement Tommy O'Brien went over.
England got on the board just before the break through Fraser Dingwall's try, but any hopes of an unlikely comeback were snuffed out by Dan Sheehan's try three minutes after the restart.
With the contest seemingly settled, England captain Maro Itoje was withdrawn early on his 100th cap before both sides traded tries in a ragged end to the game.
Ireland's win - their biggest ever in England -- put them on nine points from three games, one behind leaders France who host Italy on Sunday. England are fourth on five points.
England fall to early deficit again
Last weekend, England were 17-0 down to Scotland inside the opening 15 minutes and once more gave themselves a mountain to climb.
Jack Crowley, replacing the under-fire Sam Prendergast, kicked an early penalty before James Lowe spurned an opportunity with an uncharacteristic fumble, but England failed to capitalise on their visits to the 22.
Ford missed two simple kicks for touch and Ireland managed to keep turning the ball over under pressure, before Gibson-Park's quick tap penalty produced the first try after Baloucoune's barrelling run.
Ireland claimed the second try their dominance deserved when centre Stuart McCloskey broke free down the middle and Baloucoune went over in the corner.
England fullback Freddie Steward was shown a yellow card as Crowley lined up the conversion, which he missed, to leave the hosts 15-0 down and reduced to 14 men in almost a mirror image of their slow start against Scotland.
England struck back with the last action of the first half when Dingwall went over, but Sheehan scored a try almost immediately after Henry Pollock - making his first England start - saw yellow to put the game beyond the hosts.
Centre Ollie Lawrence pulled a try back for England before Jamie Osborne scored for the visitors with just over 10 minutes remaining. Replacement Sam Underhill added a late consolation, but by then many England fans had left the stadium.