Celtic goalkeeper Fraser Forster was handed his debut behind a defence that featured Manchester United's Phil Jones starting at centre-back for the first time at international level, while in-form Southampton duo Jay Rodriguez and Adam Lallana earned maiden caps as they flanked Wayne Rooney in attack.
But, despite a promising start with Lallana impressing, Alexis Sanchez headed the visitors into a seventh-minute lead by stealing a march on Leighton Baines, who was preferred to Ashley Cole at left-back by Hodgson.
Cole's fellow Chelsea defender Gary Cahill then ceded possession early in stoppage time as England pushed for an equaliser, allowing Sanchez to delightfully dink over Forster and condemn Hodgson's men to their first loss since last November.
"Not totally," Hodgson told ITV when asked whether his unfamiliar selections caused the reverse. "To be fair, we played against a very good team.
"From a goal down it was always going to be difficult. I thought we came back into the game well towards the end of the first half and at the start of the second half.
"But unfortunately, playing against these very skilful teams and these teams who know how to take the sting out of games, the longer the game went on there seemed to be more minor fouls, more stoppages - not helped of course by all of the changes.
"And I thought, to be frank, that Chile were the better team tonight. I thought they played very, very well.
"We were a bit unlucky to lose it by two goals to nil, the last one where we were pushing forward with the unfortunate mistake, but we learnt a lot of things tonight.
"We learnt a lot about our squad of players but also we learned a lot about what it's going to be like to play against South American opposition."
Frank Lampard was England’s captain for the game and received a commemorative golden cap before kick-off from his father Frank Snr and Geoff Hurst to celebrate bringing up 100 international appearances when England booked their place at Brazil 2014.
And the veteran midfielder reserved praise for Lallana after observing a bright and industrious beginning to the 25-year-old's own international career.
"I thought he was very lively. Both the Southampton boys deserved their place on merit with the way they're playing.
"Adam had a couple of chances and on another day he might have had two goals on his debut."
