Under Enrique, the Spaniards were beginning a new dawn following the retirement of Andres Iniesta, David Silva and Gerard Pique after a disappointing summer in Russia.
The Three Lions made a telling start, with Kieran Trippier looking to trigger a through ball to Marcus Rashford but the defence read the danger and cleared away.
A sweeping counter attack found Harry Kane playing a long ball out wide to Luke Shaw who ran down the left to swipe in a low cross for Rashford who side-footed home on 11 minutes. 1-0 to England.
The lead lasted only two minutes as La Roja responded with a clinical finish into the bottom corner from Atletico Madrid’s Saul Niguez after a cross from Rodrigo.
The Spaniards went ahead as Rodrigo scored his first international goal since March, with an easy tap-in at the near post following a well-timed free-kick by Thiago Alcantara on 32 minutes.
Known for his outstanding saves, David De Gea plucked out a header from Marcus Rashford seconds later, after a cross from out wide.
Saul closed in on his brace at the other end after a looping ball landed on his lap on the edge of the box, but his volley ended safely into the hands of Jordan Pickford.
England were forced to an early change in the second half, as Luke Shaw was forced off through injury after 53 minutes, with Danny Rose taking his spot.
Spain still looked menacing on the ball, and defensively, continued to keep Kane and company at bay with their high-line approach.
Their first change in the era of Enrique happened on 67 minutes, as Iago Aspas made way for Real Madrid’s Marco Asensio.
After struggling to adapt to the slick passing game of the Spaniards, England found a great chance to go level, but Rashford shot straight at De Gea with Kane firing the rebound into the side-netting
England looked to end strong in the final minutes, but were unable to break down the sturdy defensive wall of the 2010 World champions.
England thought they had equalised in added time when Danny Welbeck tucked home from a handling error from De Gea, only for the officials to rule that he was fouled.
The World Cup semi-finalists continued searching for the all-elusive equaliser, but Spain’s rearguard kept them out to give Enrique a debut win.