Defoe's rocket (80) ensured a measure of revenge for last month's Euro 2012 defeat, though in truth neither side bore much resemblance to those on duty in Kiev.
Still, after Phil Jagielka's fine header (27) had cancelled out a similar effort from Daniele De Rossi (15), Defoe's winner at least sent England towards the road to Rio on the back of Roy Hodgson's third straight friendly win.
With five debutants, including an excellent performance from second-half substitute John Ruddy, Michael Carrick easing himself back into the international fold and revenge, of sorts, for that quarter-final defeat, Hodgson's troops can be delighted with their efforts in Switzerland.
Fifty-two days since that shattering shoot-out defeat in Kiev, the atmosphere could not have been more different.
A 30,000-capacity stadium that was barely half full for a game few had any appetite for.
Yet, with only Ashley Young surviving from the team that started that last eight defeat, so many had a point to prove.
Three would have gone to the Finals but for injury, Carrick made himself unavailable, Tom Cleverley never had a chance to prove his worth and four were in Poland and Ukraine but had only a peripheral role.
Amongst them was Jack Butland.
The Birmingham keeper has had an amazing summer.
League Two with Cheltenham, to third choice England keeper, Olympics and now this.
Indeed, when Hodgson's squad was announced on Friday, the intention had been to send Butland back to Birmingham on Tuesday so he could feature in their Capital One Cup victory over Barnet.
Joe Hart's back injury changed those plans and after giving it some thought overnight, Hodgson plumped for Butland ahead of Ruddy, his other goalkeeper, who was also hoping to make his first appearance.
At 19 years and 158 days, it meant he became England's youngest keeper, beating the record of Billy Moon, who was 19 and 222 days when he played against Wales at Crewe in February 1888.
Not that Butland would have enjoyed the opening stages of his momentous night as Italy quickly gained the initiative.
Cesare Prandelli had named an equally experimental squad but it was one of his Euro 2012 stalwarts, De Rossi, who did the damage, rising to meet Alessandro Diamanti's corner and power it in.
Things got better for Butland after that, with the teenager producing a couple of decent saves and commanding his penalty area in a manner that suggested in a few years he will be a genuine challenger for Hart.
Indeed, England improved as a whole, with Carrick and Cleverley starting to get to grips with their roles in a three-man midfield, a new innovation for Hodgson since he succeeded Fabio Capello in May.
Adam Johnson also sparkled, although the equaliser arrived from an unlikely source just before the half hour when Jagielka's diving header found the bottom corner.
It was the Everton man's first international goal, which skipper Frank Lampard nearly built on when he curled a free-kick inches over.
Although he had happier things to occupy his mind this evening, Sir Alex Ferguson would not have been too impressed to see Davide Astori go straight through the back of Ashley Young, which led to a few choice words to the referee from the Manchester United winger.
Butland and Andy Carroll were replaced at the break, which gave Ruddy his chance.
And he could not do much more than get down brilliantly to turn away Mattia Destro's shot on the turn that was heading for the bottom corner.
Antonio Nocerino slid a superb pass through to Federico Peluso, who drove his shot into the side-netting.
Kyle Walker was at fault on both occasions, proving the Tottenham youngster is not quite the finished article even though he was last season's PFA Young Player of the Year.
Gary Cahill has a happy knack of scoring for England and thought he had another when he drove home James Milner's corner, only for the goal to be ruled out for an infringement by Joleon Lescott.
Jake Livermore became England's fourth debutant when he replaced Lampard midway through the second-half, a move which saw Carrick inherit the captaincy, and Ryan Bertrand completed the quintet of rookies.
And, after Ruddy produced another sparkling save to deny Marco Verratti, Defoe's shot exposed some sloppy keeping by Salvatore Sirigu to seal victory to ensure it was a night to remember for them all.