The in-form Barcelona forward struck in the seventh minute and again in injury time, taking his tally of goals to ten in nine games for club and country and condemning England to defeat for the first time in 11 matches.
Fifteen years after a 2-0 win on their last visit to Wembley - where Marcelo Salas got a brace of his own, Chile left with a spring in their step ahead of Tuesday's friendly game with Brazil in Toronto, having extended their own unbeaten run to ten matches. England manager Roy Hodgson, meanwhile, will hope for a more impressive showing from his side against Germany next week, when he is expected to name his strongest starting line-up.
He used Friday's game to experiment, handing debuts to Celtic goalkeeper Fraser Forster and Southampton pair Adam Lallana and Jay Rodriguez, while Manchester United's Phil Jones started at centre-back.
Chile were without injured midfielder Arturo Vidal and the visitors initially looked set for a long night, with goalkeeper Claudio Bravo athletically repelling a header from Jones and then preventing one of his defenders from putting through his own goal.
However, the visitors' very first attack yielded a goal, with Sanchez stealing in front of Leighton Baines to head home Eugenio Mena's left-wing cross at the end of an incisive counter-attack. The unfamiliarity in the England line-up, allied with Chile's adventurousness with the ball, made for an open first half.
Home captain Frank Lampard, presented with a golden cap before kick-off for making 100 international appearances, saw a 30-yard free-kick tipped over by Bravo, who also beat away a rasping drive from Jack Wilshere.
Chile's Britain-based contingent threatened Forster's goal, meanwhile, with the Celtic goalkeeper saving from Wigan Athletic's Jean Beausejour and seeing Cardiff City's Gary Medel head over the bar. England continued to press though, and after Jones went close with a deft volley from a corner, Wayne Rooney teed up Lallana for a shot that was deflected wide.
An anticipated raft of substitutions drew all of the sting from the game in the second half. Hodgson introduced Chris Smalling, Andros Townsend, Jordan Henderson, Tom Cleverley and Ross Barkley, but they spent long periods chasing shadows as Chile's nimble technicians smoothly exchanged passes.
A wayward 30-yard shot from Glen Johnson was the hosts' only effort of note after the break and it was Sanchez who had the final say, racing clear of the England defence and coolly chipping Forster.