Alexis Sanchez fired a brace as Chile condemned England to their first Wembley defeat under Roy Hodgson.
Barcelona star Sanchez produced a man of the match display to put the hosts to the sword a year and a day since a 4-2 reverse to Sweden.
On a crisp winter's evening, Hodgson named three debutants in his starting eleven, with Southampton pair Adam Lallana and Jay Rodriguez joining Celtic goalkeeper Fraser Forster in making their international bows.
It was also a night that saw Frank Lampard, wearing the captain's armband, receive a golden cap to commemorate becoming only the eighth player to reach 100 appearances for England.
Hodgson made eight changes to the side that beat Poland last month to secure qualification for next summer's World Cup in Brazil.
In his programme notes, the England manager described Jorge Sampaoli's Chile team as "formidable opponents" -- and as soon as the whistle sounded it became evident his observation was accurate.
After a bright opening in which Phil Jones tested Claudio Bravo in the Chile goal, the hosts enjoyed much of the ball and looked threatening going forward.
Wayne Rooney found James Milner with an intelligent pass and set the Manchester City man free down the right.
The midfielder fired a low cross into the danger area and in his attempt to clear Marcos Gonzalez almost diverted the ball into his own net and but for an instinctive save by Bravo, England would have found themselves ahead.
But the Three Lions' early dominance stalled as Chile broke into their half with their first signs of intent on seven minutes.
Mauricio Isla played an exquisite pass in behind the England backline that found Sanchez free in the box and he set up Charles Aranguiz, who had a clear sight at goal.
Only a brave block by Jones prevented Forster being called into action for the first time, or so he thought as seconds later he was picking the ball out of his net.
England failed to clear their lines and Eugenio Mena found himself in space on the left. He picked out Sanchez who lost his marker and met the inch-perfect cross with a powerful low header past Forster.
A frantic spell followed as England looked to hit back immediately.
Milner had a fierce shot well-parried by Bravo before Forster got a strong hand to a strong Jean Beausejour effort moments later.
Lampard then saw a 30-yard effort from a free-kick expertly tipped over the bar by an outstretched Bravo. This was proving to be anything but an exhibition match as both teams went for the jugular.
Just after the half hour mark, the Chileans produced a stunning display of counter-attacking football from their own corner flag which led to Beausejour bearing down on Forster's goal.
Forster did well to make himself big and delay the Wigan Athletic man's shot, before the chance fizzled out but it was a warning to England.
As the half drew to a close, Hodgson's men struggled to find their rhythm and maintain possession for any sustained period. However, seconds before the break Jack Wilshere found himself in space in the centre of the field.
He picked out Rooney with a perfectly weighted pass and the Manchester United star beat his man and found Lallana in space in the box.
Unfortunately for England, the Southampton forward could not quite get the ball out from under his feet and his shot was blocked by the Chile defence before going wide of the goal.
England began the second half brightly, with Rooney breaking free on the left to force a corner. They kept knocking on the door but the Three Lions could not break through a resolute Chile defence.
Hodgson decided it was time to inject some fresh legs into the game. Jones was replaced by club team-mate Chris Smalling and Rodriguez came off for Andros Townsend, who had an almost immediate impact.
The Tottenham man picked up the ball wide on the right and turned Mena before playing the ball into Wilshere, who was subsequently bright down on the edge of the box. Leighton Baines' seemingly goal-bound free-kick clipped the wall and went out for a corner.
By this time Jermain Defoe, Tom Cleverley, Jordan Henderson and Ross Barkley had been introduced as England stepped up the tempo.
But the visitors sought to slow the pace of the game down, get men behind the ball and prepare to hit back on the counter-attack.
And their game plan succeeded as they claimed a second after Marcelo Diaz picked up a loose ball and found Sanchez, who darted through on goal before dinking the ball over Forster to score his second of the match and wrap the game up.
Hodgson will of course be unhappy to have seen his unbeaten home record disappear into the cold November air, but will take solace in the fact he's been able to blood three newcomers to the international scene as he continues his audition process for the World Cup in Brazil next summer.
Now full focus turns to the visit of Germany in four days' time.