Thomas Tuchel had sprung a surprise by replacing Jordan Pickford with James Trafford, in what could be considered a defining moment in the careers of both.
Five changes for the hosts
Luis de la Fuente had made five changes for the hosts, no doubt wary of the threat that England would pose.
The Three Lions had won their last nine away matches, and did beat La Roja the last time that they played them in Spain back in 2018.
For two teams evidently in such good form, the game was going to be decided by the smallest details and the one-on-one battles that would emerge.
An incredibly fast start from the visitors, in which a vibrant high press was in evidence and often overwhelmed the Spanish, also saw Anthony Gordon heavily involved, with his direct opponent, Marc Pubill, unable to get a hand on him in the opening exchanges.
Lewis Hall's battle against Lamine Yamal was always going to be one to watch, too, after the Englishman had kept the Spaniard quiet when they faced each other in last season's Champions League.
Fast start from England
Indeed, it wasn't until almost a quarter of an hour had been played that Lamine had his first run at Hall, so on top were the Three Lions prior to that moment.
Lamine and his teammates could do nothing about Hall's brilliant, mazy run, which almost helped bring about the game's first goal, and the pair were involved again shortly after when the Englishman was penalised for bringing the talented teen down just outside the area.
With two dribbles attempted and three of four duels won in the opening 23 minutes alone, Lamine was Spain's busiest player, and his influence grew as the half continued, with the hosts also managing 76% possession leading into the 30-minute mark.
The tireless running of Elliot Anderson, Jude Bellingham and Declan Rice was a real feature of England's forward play, and it helped to ensure that Alex Baena couldn't build up his own head of steam - just 77.8% pass completion was one of the worst on the pitch.
Kane scores again
In his first one-on-one with Harry Kane, FIFA Golden Boy, Pau Cubarsi, who was the only Spaniard with a 100% pass completion, chopped down the England captain to hand the visitors a penalty right on half-time.
Ballon d'Or winner Kane smashed home the spot-kick, making him the first Englishman since Tom Finney in the 1950s to score in seven successive away matches.
No one could argue that England didn't fully deserve their lead, as up to then they'd stopped the hosts from getting a single shot on target. Even Lamine could only manage a 50% pass completion rate in the first half, as Hall continued to get the upper hand in their duels.
Cubarsi's reward was to be hooked at the break as part of a triple change from de la Fuente, who clearly wanted to see a reaction.
Konsa and White stun the Spanish
Though Spain's play had a bit more zip to it, they were still being swarmed by a ravenous English attack. When Lamine threatened, which only happened briefly, Hall was again up to the task and, ably assisted by Gordon, they were able to exert themselves once more.
The stadium was stunned into silence when Ezri Konsa powered home a header from a corner, which was a fourth effort from the away side, against a team that rarely gives up that many chances in a game.
England's physicality, as much as their prowess in front of goal, was the one thing that had knocked the Spanish out of their stride, and just four minutes later, Ben White scored a third England goal after another incisive move.
With an hour gone, the hosts still hadn't managed a shot on target, compared to five from the Three Lions, and Lamine's yellow card evidenced his own personal frustration.
Red mist descends for Anderson
Bellingham had begun to emerge as the game's main player with five touches in the Spain box, but he was always going to find things difficult in the final half hour once his midfield partner, Anderson, was red-carded for a professional foul on Lamine. Mikel Oyarzabal scored from the resulting penalty.
The lifeline saw an immediate change of atmosphere, both on the pitch and in the stands.
Gordon lost the ball in midfield to club colleagues Pedri and Fermin, before the ball was fizzed to Lamine and then crossed for Nico Williams, who made no mistake, bringing Spain to within a goal of clawing back a three-goal deficit.
But Bellingham's five dribbles completed and 10 one-on-one duels successfully managed saw him as a one-man wrecking ball against wave after wave of attacks from the hosts.
Trafford's stunning stops
From having four shots and none on target on the hour, by the 80th minute the Spanish had taken 11 shots with three on target, and Thomas Tuchel's side could do nothing about the incessant nature of the attacking as Spain sought to preserve their unbeaten record.
Both Kane and Bellingham were subbed off with eight minutes to play, with Dominic Calvert-Lewin tasked with holding the ball in midfield and attack when given the chance.
Though Lamine was seeing more of the ball late on, getting four shots away as well as having four dribbles and contesting 11 one-on-ones, Hall was still matching his output, and their respective Flashscore ratings of 8.8 and 7.7 showed this.
The Englishman ended with stunning figures that included winning back possession on three separate occasions, winning eight of his 11 one-on-ones, and completing five of his six dribbles.
Seven clearances, two interceptions and two fouls won added to a super individual performance against one of the world's best players.
Every England player had done their part, and that includes goalkeeper Trafford, who had little to do up until the hour mark, but who made two stunning saves in injury time, which were as much a reason why the Three Lions roared in Madrid as anything else.
A 10th away win in a row was a record that England may not have expected, but they fully deserved.
Check out the match stats here.
