Elliot Anderson, Marc Guéhi and Nico O’Reilly all started for the Three Lions in their first game since finishing third at the World Cup in the summer.
Spain won that tournament and were ahead inside two minutes when Guéhi was caught on the ball by Lamine Yamal who clipped a shot home off the far post.
They thought they were 2-0 up ahead shortly after when former City striker Ferran Torres tapped in but was shown to be offside.
He was then denied by former Blues Academy keeper James Trafford with Spain looking most likely to add the scoresheet.
But the game turned on its head with two England goals in four minutes just before half-time.
Barcelona forward Anthony Gordon finished smartly after a quick break led by Real Madrid’s Jude Bellingham.
And moments later, O’Reilly escaped down the left hand flank and picked out a cross for Harry Kane that crossed the line via Marc Cucurella’s attempted clearance.
Kane missed a golden opportunity to double England’s lead from the penalty spot after Bellingham was caught by Rodri, but slipped as he took it, kicking the ball against his standing foot and onto the bar.
Spain hit back from a misplaced O’Reilly pass, when Álex Baena curled in a smart strike from the edge of the box on the hour mark.
And 15 minutes later, Mikel Oyarzabal’s exquisite dinked finish put them back in front.
In the other game in Group A, Joško Gvardiol and Mateo Kovačić helped Croatia to a winning start.
The City duo played 90 minutes in a 2-1 victory over Czechia in Prague with Luka Modrić and Marco Pašalić on target.
