Harry Maguire and Reece James saw red as England were beaten 1-0 by Denmark at Wembley to fall from top spot to third in their Nations League group.
England were given a mountain to climb with two big incidents in the space of three first-half minutes; first Maguire was sent off for a second yellow card (32), before Christian Eriksen put Denmark ahead from the spot (35) after Kyle Walker had fouled Thomas Delaney in the penalty area, a soft award from card-happy referee Jesus Gil Manzano.
Leicester goalkeeper Kasper Schmeichel kept Denmark ahead in the second half with a world-class save from Mason Mount's close-range header, while Simon Kjaer's brilliant last-gasp block denied Conor Coady late on.
James was also sent off after full-time for his protestations towards the officials, as England suffered only their second competitive defeat at home in 13 years.
The result, paired with Belgium's win over Iceland, means England must avoid defeat away at Belgium in their next Nations League clash on November 15 to stand a chance of winning their group and repeat their successful 2018 campaign.
How England shot themselves in foot on grim night
Though England were finding space down the right flank through Mount and James early on, they struggled to create any clear-cut chances in the first half as Denmark's stubborn defence stood firm.
England's task was made more difficult in a calamitous three-minute spell as Maguire - booked in the fifth minute for a late challenge on Yussuf Poulsen - received a second booking after his poor touch forced him to stretch to retrieve the ball, catching Kasper Dolberg on the follow through.
Spanish referee Manzano did not hesitate in showing a second yellow, and just two minutes later he awarded Denmark a dubious penalty.
As Walker moved in to challenge Delaney just inside the box, Jordan Pickford rushed out and called for the ball, prompting the Manchester City man to first hold back, and then move in to challenge Delaney as he realised Pickford would not make it. Walker then slightly caught Delaney on his follow through, but with the ball already gone, and no VAR, the award was questionable.
On his 100th cap, Eriksen converted down the middle for the opener.
That prompted a change for England as Ainsley Maitland-Niles made way for Tyrone Mings, and though Denmark failed to create many chances thereafter, the hosts couldn't find a breakthrough.
Their best chance fell to Mount, who received Harry Kane's knockdown from a corner six yards out, only to see his point-blank header wonderfully tipped away by the left hand of Schmeichel.
Daniel Wass then headed over unmarked at the other end from some flat-footed Walker marking, but England still had a chance to level in stoppage time as Conor Coady's goalbound header was blocked superbly by Kjaer inside the six-yard box.
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England's frustrations boiled over at full-time as James was dismissed on a grim night for Gareth Southgate, a night of mistakes just three days after beating the world's top-ranked side.
Southgate made five changes from the 2-1 victory over Belgium on Sunday, two enforced with Dier and Trippier unavailable and coming out for Coady and Maitland-Niles.
James replaced Alexander-Arnold, Phillips was in for Henderson, and Harry Kane returned in place of Dominic Calvert-Lewin.
Mason Mount keeps his place, with Jack Grealish remaining on the bench.
Denmark were unchanged following their 3-0 win against Iceland on Sunday
"The biggest doubt I have about England winning a tournament next year is individual errors," said Sky Sports' Gary Neville on commentary, and now their success in this Nations League is out of their hands as they look ahead to November's internationals.
Southgate proud of England performance
England manager Gareth Southgate on Sky Sports:
"I was very proud of the performance. I thought we were excellent for the opening period with 11 men, we really moved the ball round and causing them all sorts of problems on our right-hand side.
"The sending off obviously alters everything, and the penalty shortly afterwards, but with 10 I thought we showed great resilience. I thought we gave a great example of how you should play with 10. The team dug and defended as a solid unit.
"I couldn't be prouder of what the players have given, not only tonight, but over the last 10 days. We've had to deal with any manner of interruptions, changes we've had to make, so we come through as a more resilient group."
On James sending off: "The referee says he's sent him off for dissent, and of course that's a lesson he's got to learn, he's a young player. But I thought he had an incredible debut. He's impressed me all week, and until that moment he'd shown great maturity."
On discipline within squad: "We've put ourselves in unnecessary situations off the field. I think the reds we've had for Kyle in Iceland and Harry here are both occasions where one yellow is justified, the other, not so certain.
"If we go to 10 in a tournament, historically that means we're out, especially if we're playing for an hour, and that's what I'm so pleased with their reaction at the end."
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England manager Gareth Southgate on Sky Sports:
"For me, he is a top player and a massive part of what we do. He is having a period where he is getting a lot of stick thrown his way. He is big enough to deal with that and he will be stronger for it. He has our full support and I know his club will be the same
"He will be getting all sorts. He has been getting all sorts for a while from some people who should know better. None of us like to be at the centre of that sort of summer, do they?
"He is having one of those periods where things are going against him but you have to hang on in there and things will turn."
Sky Sports' Gary Neville:
"It sums up his last four to six weeks. It is a terrible time for him.
"Watching that Tottenham versus Manchester United game 10 days ago when obviously Harry Maguire had a bad time, you were thinking that he needed international duty just to get away, a different environment. But it has not served him well.
"He will go back in as bad of a place as he came."
Sky Sports' Jamie Redknapp:
"I think his confidence is on the floor, it's obvious. You don't become captain of Manchester United unless you've got a lot about you. You have a presence and a quality that people like, they admire - and right now, his confidence is on the floor.
"Everything I hear about him, he's a really good lad, but he's making mistakes that I didn't see him make a few years go. He's got a lot on his mind, we can try and brush it aside and some players can handle it, it doesn't bother them and the pitch is their sanctuary.
"But others can't. They go on there and carry it onto the pitch. You don't know what's going on in people's minds, we're all very quick to judge."
- This was only England's third home defeat in their last 50 competitive internationals on home soil (W41 D6), also losing against Croatia in November 2007 and Spain in September 2018 in this run.
- Harry Maguire became the third player to be sent off for England at Wembley, after Paul Scholes (1999 vs Sweden) and Steven Gerrard (2012 vs Ukraine).
- England received a red card and conceded a penalty goal in the same international for the first time since their last 16 match at the 1998 World Cup vs Argentina.
- Harry Maguire's red card after 31 minutes was the second earliest by an England player in an international, after Rob Green vs Ukraine in October 2009 (14 minutes).
With New Zealand cancelling their trip to Wembley for the proposed friendly on November 12, England's next arranged match comes away at Belgium on Saturday November 15 at 7.45pm in the Nations League, before hosting Iceland on November 18.