Spain could not respond until shortly before the hour mark when substitute Paco Alcacer made an immediate impact, but Sergio Ramos's header to reduce the deficit to one came too late for them to force a comeback.
Find out how all of the action unfolded on a remarkable night of international football courtesy of Sports Mole's minute-by-minute updates below.
The downpour in the city today has led to some doubts over whether the match will even take place this evening, but as things stand we are still set for a 7.45pm kickoff in a match which could see Spain clinch top spot and England's hopes of progress ended once and for all.
We will get to all that a little later, but first let's check out the team news...
Well, we'll start with England and the first thing to note is that Gareth Southgate has once again gone with a four-man defence - a formation he utilised for the first time in a year for Friday's stalemate with Croatia.
It is a 4-3-3 system named by Southgate tonight, with just three changes from that draw with Croatia - two of which are enforced.
There is also a change at right-back, with Kieran Trippier replacing Kyle Walker in the defence. The Man City man drops to the bench, which is inexperienced to say the least and contains as many as five uncapped players.
The starting XI is not exactly laden with caps either, though, with Ben Chilwell making just his second England start and Winks winning only his second cap.
Kane has since gone six England games without a goal - his joint-longest drought at international level. Raheem Sterling is another who has been firing blanks for his country, although his drought stretches back significantly longer - to October 2015.
Indeed, Sterling has now gone 1,102 days and 27 games without an England goal, with just four of his 34 shots in that time even going on target.
Jonny usually plays at left-back for Wolves, but he is right footed and will start on the right tonight, replacing Cesar Azpilicueta in the team. There is a Chelsea defender on the opposite flank, though, as Marcos Alonso comes in for Jose Gaya.
Asensio, incidentally, is the leading assist-maker in the Nations League so far, having notched four in the 6-0 rout of Croatia alone. Asensio was also on the scoresheet in that match, so he is one England will need to keep a particularly close eye on tonight.
Alcacer can rightly feel hard done by with that, having scored twice against Wales last time out and also made a blistering start to the season with Borussia Dortmund, leading the Bundesliga scoring charts. Indeed, Alcacer has scored nine goals in five matches for club and country this season, averaging a goal every 27 minutes.
Busquets provides plenty more experience as he prepares for his 110th international appearance, and between them they have won 55 more caps than the entire England starting XI combined.
Enrique boasts a 100% record at the helm so far, with three wins from three and 12 goals in that time - an average of four per game - re-establishing Spain as a force to be reckoned with on the international stage.
That appeared to be as much to do with matters off the pitch as on it, though, with Spain sacking head coach Julen Lopetegui on the eve of the tournament after it emerged that he had agreed to join Real Madrid after the World Cup.
Fernando Hierro was drafted in as an emergency replacement for La Roja, but ultimately their journey ended in the last 16.
It is now 27 matches since that loss in the last 16 of Euro 2016, since when they have won 18 and drawn nine of their outings after 90 minutes. Try telling any Spanish player that their penalty shootout exit to Russia doesn't count as a defeat, though.
A trip to Wembley last month was not the easiest start for Enrique in the Spain dugout, particularly after some time out from the game, but his side came from behind to win and then made a real statement by hammering World Cup runners-up Croatia 6-0 to take complete control of their Nations League group.
Spain were three goals to the good within half an hour and looked capable of racking up a cricket score, but they took their foot off the pedal a little without surrendering any control of the game, with Wales eventually clawing back a consolation right at the death.
Indeed, even a draw should be enough to effectively wrap up Spain's place in the next round, with Luis Enrique's side currently sitting five points clear of both Croatia and England, having beaten both of them last month.
In all competitions, Spain have won eight and lost none of their last 10 home games - averaged 4.2 goals per game in that time - and at this particular stadium they have won 12 of their 13 matches, although this is their first game at the home of Real Betis since 1995.
Even so, Gareth Southgate has repeatedly expressed his belief in this young group of players, and tonight will at the very least give them a chance to gain some much-needed international experience against some of the best football has to offer at the moment.
Even victory leaves them with plenty of work still to do, as they would need to then beat Croatia next month and hope that Spain lose to the World Cup runners-up if they are to overhaul La Roja and reach the Finals.
It was an eerie atmosphere in Rijeka as the match was played behind closed doors, and ordinarily an away draw at the World Cup runners-up would be considered a decent result. However, this was a Croatia team without the home crowd behind them and coming off the back of a 6-0 defeat to Spain in their last outing.
That result left Southgate's side with only one point from their opening two games of the tournament, having also lost at home to tonight's opponents last month - squandering a one-goal lead at Wembley.
Indeed, the Three Lions are now winless in their last four competitive matches - losing three of those - and tonight could go five in a row for the first time since October 1992 under Graham Taylor.
However, England aspire to be amongst the best and these are the teams they will need to start beating if they are to reach that level.
Should they pick up a draw or a win tonight then it would be their longest away unbeaten streak for more than three years, although Southgate has already admitted in the buildup to this match that his players are "lacking psychological freshness" given the short break before the end of the World Cup and the start of the Premier League.
Spain are a team in really good form right now and it is certainly hard to see them losing this game. They have the superior quality on the field and the home advantage too, so it is going to have to be a Spain win tonight.
SPORTS MOLE SAYS: Spain 2-0 England
England's most recent victory over La Roja came in November 2011, when Spain were still world champions, as Frank Lampard scored the only goal of the game in a 1-0 win at Wembley.
The Three Lions do, however, edged the overall head-to-head record with 13 wins to Spain's 10.
However, Lineker remains the last England player to score in an away international against Spain, with the Three Lions drawing blanks in each of their four visits since.
Incidentally, the last England goalkeeper to keep a clean sheet in an away game against Spain was Peter Shilton in May 1980, when England won 2-0.
England's last visit to Spain, meanwhile, saw them beaten 2-0 in November 2015 courtesy of goals from Mario and Santi Cazorla.
SPAIN STARTING XI: De Gea; Jonny, Ramos, Nacho, Alonso; Busquets, Thiago, Saul; Aspas, Rodrigo, Asensio
ENGLAND STARTING XI: Pickford; Trippier, Gomez, Maguire, Chilwell; Winks, Dier, Barkley; Sterling, Kane, Rashford
It is a brilliant finish from the Man City forward too, as he picks out the top corner in emphatic style - similar to Michael Owen's finish against Argentina at the 1998 World Cup.
It comes at the end of a sweeping England break too, with Rashford playing the final ball into the path of Sterling, who was clear of the defence and made absolutely no mistake with his finish!
A long ball forward is picked up by Kane, who threads a lovely pass in behind the defence for Rashford. The United man takes a touch before firing his finish past his clubmate De Gea to send the away fans wild!
Spain just cannot get out as England win every second ball in quick succession, eventually allowing Barkley to float a ball over for Kane. Kane turns the ball back into the middle where Sterling is unmarked to sweep it home.
Terrible defending from Spain, but another lovely move from England.
The visitors lead 3-0 at the halfway stage having cut Spain open at times, and it would take a remarkable comeback and collapse for Spain to drag themselves back into this match.
The front three were all involved as Kane collected a pass from Pickford before playing it out for Rashford, who in turn threaded a pinpoint pass through for Sterling. The Man City man raced through on goal and then picked out the top corner with a sensational finish.
Rashford's first touch in the area was perfect, and he then had the composure to apply the finish as he joined Sterling in scoring his first ever away goal for his country.
Spain could not get out of their own third in the buildup to the goal and Barkley lofted a lovely pass into the box for Kane, who was again unselfish to knock it back across goal for Sterling to apply the simple finish.
It is poor defending from England as they leave him completely unmarked at the back post, but there is still plenty to do. Alcacer does it well, though, flicking his header into the far corner.
Pickford tries to be too clever on the ball and is caught in possession by Rodrigo, before tugging him back in the area and sliding in to make a goal-saving tackle. The final challenge is actually good, but the initial tug back should have been punished and England have got away with one in a huge way there.
Spain were stunned by a first-half blitz from England as goals from Raheem Sterling either side of a Marcus Rashford strike put them in complete control of the match, and Spain could only muster an Alcacer header in response before Ramos pulled a second back with the final action of a thrilling match.
Thank you very much for joining Sports Mole for this remarkable night of international football as England produce a stunning display to beat Spain in Seville. I will leave you with our match report, and be sure to stick around for reaction too.
From me, though, it is goodbye for now!