Ireland kept their hopes of a Six Nations title alive as they finally saw off a valiant, spirited England who played 78 minutes with 14 men after Charlie Ewels' red card.
Ewels was dismissed with just 82 seconds on the clock after clashing heads with James Ryan in an attempted tackle.
Ireland, the pre-match favourites, seemed set for a procession. Instead they were dragged into a desperate, captivating dogfight by the depleted hosts.
James Lowe and Hugo Keenan scored first-half tries, but Marcus Smith's boot kept England in touch with three penalties for a 15-9 scoreline at the break.
Smith potted another two to bring England level after the hour. It seemed an extraordinary heist may be on as Twickenham roared like it rarely has before.
Ireland though finally made their advantage and strength in depth pay as they came on strong late on with Jack Conan and Finlay Bealham crossing to squash the resistance.
The defeat ends England's hopes of winning the Six Nations, but they could have a say in the trophy's destination. Denying France in Paris next weekend would open the door for Ireland, who take on Scotland in the final round.
Ewels' red fuels England passion
The pre-match pyrotechnics were still floating on the Twickenham air when the momentum swung decisively in Ireland's favour.
Second row Ewels' tackle on Ryan was more clumsy than callous, but, whether he was trying to strip the ball or hold his man up in the tackle, his body height was high and risky.
The clash of heads was nasty, the mitigation non-existent. To the consternation of the crowd, French referee Mathieu Raynal brandished red after just 82 seconds - the earliest dismissal in the Championship's 139-year history.
Ewels trudged to the touchline, Johnny Sexton slotted the penalty, and jeers rolled down from all sides.
After the disbelief, came the defiance.
England raged against perceived injustice, throwing caution to the wind and their bodies into the fray.
Harry Randall tapped and went, Maro Itoje swarmed over the line-out and breakdown, Ellis Genge milked opposing prop Tadhg Furlong for a string of penalties as wing Jack Nowell filled in at flanker at the scrum.
Coach Eddie Jones had cast England as the underdog in the build-up and, with their odds dramatically lengthened, his team and their crowd seemed to relish their status.
Shortly after Ewels' departure, wing Lowe trotted in following good work from hooker Dan Sheehan and flanker Josh van der Flier to put Ireland into an 8-0 lead.
But the visitors could not make the cold logic of their superior numbers count.
Referee Raynal ruled out a Caelan Doris score with a highly debatable knock-on call, while the penalty count was 9-4 in favour of England at the break.
Keenan's short-range surge on 37 minutes ensured Ireland reached half-time with a 15-9 lead, but captain Sexton was in animated discussion with Raynal all the way down the tunnel.
Sexton's concern was justified. England refused to submit. Ireland continued to fumble their advantage.
Tadhg Beirne forced a pass and knocked on when another phase would surely have unpicked the England defence.
England revelled in the error. They whooped and hollered as they sent the Ireland front row, badly missing the injured Andrew Porter, into reverse once again. Hooker Jamie George exhorted more volume from the crowd and slowly the apparently impossible became tantalising feasible.
Smith slotted penalties in the 53rd and 61st minutes to finally bring parity on the scoreboard. Doubt gnawed at Ireland, England grew shirt sizes.
But the final quarter was always going to be the hardest. Ireland unloaded a bench that contained four British and Irish Lions, fatigue ambushed England and the home fans' dream withered.
Itoje escaped more severe punishment for a cynical piece of breakdown skulduggery inside his own five metre, while Doris butchered a glorious chance to put Conor Murray in under the posts.
But the dam finally burst as Conan crashed over in the wake of Andrew Conway's break and Bealham picked and burrowed through some flagging white shirts in the final four minutes.
The two teams took a lap of appreciation after the final whistle, accepting applause for a thrilling spectacle that few saw coming after Ewels' early dismissal.
The result is only England's third loss in their past 26 Six Nations games at home and Ireland's second win at Twickenham since 2010.
Man of the match - Hugo Keenan (Ireland)
Line-ups
England: Steward; Malins, Marchant, Slade, Nowell; Smith, Randall; Genge, George, Sinckler, Itoje, Ewels, Lawes, Curry, Simmonds.
Replacements: Ford for Steward (79), Daly for Marchant (69), Youngs for Randall (52), Marler for Genge (67), Blamire for George (79), Stuart for Sinckler (38), Dombrandt for Curry (14), Launchbury for Dombrandt (67).
Sent Off: Ewels (2).
Ireland: Keenan; Conway, Ringrose, Aki, Lowe; Sexton, Gibson-Park; Healy, Sheehan, Furlong, Beirne, Ryan, O'Mahony, Van der Flier, Doris.
Replacements: Henshaw for Aki (66), Carbery for Sexton (79), Murray for Gibson-Park (67), Kilcoyne for Healy (53), Herring for Sheehan (53), Bealham for Furlong (73), Henderson for Ryan (2), Conan for O'Mahony (61).
Referee: Mathieu Raynal (France)
Touch judges: Mike Adamson (Scotland) & Pierre Brousset (France)
TMO: Marius Jonker (South Africa)