The Three Lions scored all of their goals during a remarkable first-half blitz as they stormed into what proved to be an unassailable lead in Seville, debunking a host of pre-match statistics to keep their hopes of reaching the Nations League Finals alive.
Raheem Sterling scored either side of a Marcus Rashford strike to put the youngest England starting lineup since 1959 into a commanding lead, and Spain could only provide headers from Paco Alcacer and Sergio Ramos in response as their 100% start under new boss Luis Enrique was ended by their first defeat inside normal time since Euro 2016.
It is also Spain's first defeat in a competitive home match since June 2003 - a run of 38 matches which had included 34 wins - and England's first win away to Spain for 31 years.
Despite the way the first half would pan out, it was Spain that made the brighter start to the match and Thiago Alcantara squandered a big chance after only four minutes when his first-time effort from a corner routine was deflected narrowly wide.
The resultant corner almost led to an opener for Spain too as Ramos flicked the ball on for Marcos Alonso at the back post, but the Chelsea defender's hook back inside struck a prone Jordan Pickford, who had gone to ground after Ramos's initial touch.
Marco Asensio then drew another stop from Pickford with a tame toe-poke, but the hosts' bright start soon faded and the rest of the opening 45 minutes belonged to England.
The visitors took the lead in the 16th minute as Sterling brought an emphatic end to his 1,102-day, 27-game goal drought at international level with his first England strike since October 2015 - and the first England had scored in an away game against Spain since 1987.
It was an incisive move from England as Pickford, Harry Kane and Rashford combined, with the latter threading the final ball through for Sterling, who left David de Gea no chance with a pinpoint finish into the top corner - his first ever away goal for his country.
Pickford was called into action to deny Thiago's whipped free kick midway through the half, but England gained a greater degree of control over the game with their second goal just before half time.
This time it was route one play as Kane collected a long ball forward before slicing the Spain defence open with an incisive pass to find Rashford, who took a touch and stroked his finish past Manchester United teammate De Gea in the Spain goal.
It was also Rashford's first away goal for England, and the first time any visiting team had built a two-goal lead over Spain since 1999, and things only got better nine minutes later as Gareth Southgate's side remarkably added a third to their tally.
Spain struggled to get out of their own third and England piled the pressure on, and that eventually led to Ross Barkley lifting a clever pass over the top for Kane, who turned it back inside to set up Sterling for a simple finish.
The goal saw Sterling score two and Kane assist two in a game for the first time in their respective England careers, and it was also the first time that Spain had ever conceded three goals in a competitive home match, and only the second time they had conceded three first-half goals at home in their entire history.
It made for an astonishing half-time scoreline which had the Benito Villamarin stunned, but Enrique opted against making any changes during the interval and his side quickly began searching for a response upon the restart.
Saul Niguez fired one inventive volley over the crossbar before Joe Gomez made a crucial block to send Asensio's shot on the turn into the side-netting - an effort some sections of the crowd thought had snuck in at the near post.
England were denied a free kick in a dangerous area 10 minutes into the half and Spain wasted no time in listening to the visitors' appeals, with Saul testing Pickford while Sterling still lay hurt at the other end of the field.
Enrique did turn to his bench shortly before the hour mark as Dani Ceballos and Alcacer were introduced, and the latter made an immediate impact by pulling a goal back with his first touch of the match.
The Bundesliga top scorer had averaged a goal every 27 minutes for club and country this season, and it took him less than one minute to get on the scoresheet tonight as he was left unmarked from a corner to flick a fine header past Pickford.
Pickford's role in conceding the corner was questioned, and the England keeper almost made a much clearer blunder just five minutes later when he was caught in possession inside his own area by Rodrigo Moreno.
The Everton shot-stopper got back to make a last-ditch sliding challenge, but not without dragging Rodrigo back and Spain were justifiably incensed at the referee's decision not to award a penalty - which would have also forced a red card.
England did begin to settle down again as the second half wore on, and they managed to limit Spain to off-target long-range shots until the closing stages of the match, with Asensio coming closest when his low drive zipped narrowly past the post.
Asensio did draw a save from the keeper with two minutes remaining of half time, and Pickford's parry was straight into the path of substitute striker Alvaro Morata, who could not react in time as the ball bounced off him and behind for a goal kick.
Nathaniel Chalobah came on for a late England debut as the fourth official indicated seven minutes of stoppage time, but England kept Spain at bay until the last of those, when Alonso rose highest inside the area to plant a header against the crossbar.
The woodwork would not come to the visitors' rescue just seconds later when Ramos reduced the deficit to one with a diving header, but it was too little too late for the hosts as that proved to be the final touch of the game.
The result sees England move to within two points of Spain in the Nations League Group A4, although they must still hope for a Croatia win over La Roja and then to beat Croatia themselves next month to make it into the Finals above Enrique's side.
It also ends Spain's 27-match unbeaten streak inside normal time - the longest run in international football heading into the game - as they are denied the chance to seal their Finals place with a game to spare.
SPAIN (4-3-3) De Gea; Jonny, Nacho, Ramos, Alonso; Thiago, Busquets, Saul (Alcacer 57'); Aspas (Ceballos 57'), Rodrigo (Morata 72'), Asensio
ENGLAND (4-3-3): Pickford; Trippier (Alexander-Arnold 85'), Gomez, Maguire, Chilwell; Winks (Chalobah 90'), Dier, Barkley (Walker 76'); Sterling, Kane, Rashford