Luis Enrique's side have won both of their Group A4 matches so far, and Friday night's draw between Croatia and England in Rijeka means that only a win will keep the Three Lions's hopes of progress alive.
The memories of tumult surrounding this summer's World Cup are beginning to fade for Spain as they re-establish themselves as one of world football's major forces, and Monday provides them with another chance to continue their recovery.
It has been a quick recovery so far, too; new manager Luis Enrique has stabilised things during his three matches at the helm, after Julen Lopetegui was discarded on the eve of the World Cup and Fernando Hierro forced to pick up the pieces.
Spain's record at major tournaments has been poor since their unprecedented run of three trophies in a row came to an end, and while the UEFA Nations League will not be regarded as a major tournament, there is still silverware up for grabs and Spain look intent on claiming it.
La Roja are the leading scorers in the competition so far, helped largely by their thumping 6-0 win over World Cup runners-up Croatia last month - their most recent outing in the Nations League.
The rout of Croatia made it two wins from their first two games, and the memories of their opener - a come-from-behind 2-1 win over England at Wembley - will still be fresh heading into Monday's match.
Spain do not appear to have slowed down in the interim, and their 4-1 victory over Wales in Cardiff on Thursday night was another supremely comfortable triumph, with the final scoreline flattering the hosts if anything.
It is now 27 matches since Spain lost a match inside normal time, winning 18 of those in a run which stretches back to their Euro 2016 exit - although of course they did lose on penalties to hosts Russia at this summer's World Cup.
The summer of 2016 was also the last time Spain were beaten on home soil, a shock defeat to Georgia which has since been followed up by eight wins and two draws, during which time they have scored 42 goals and conceded just five.
Not since 1995 have they played at the Benito Villamarin - home of Real Betis - although they boast a formidable record here with 12 wins from their 13 matches.
Recent Nations League form: WW
Recent form (all competitions): WDLWWW
England will have been hoping for a happier World Cup homecoming when they welcomed Spain to Wembley last month, but instead they were brought back down to earth with defeat on home soil.
Of course, given the choice between a World Cup semi-final and a poor UEFA Nations League showing - even relegation - fans would always choose the former, but England still need to show that they can compete with the best if they are to build on their momentum from Russia.
It has been a mixed bag since their return from this summer's tournament, with that home defeat to Spain being followed by victory over Switzerland three days later and a goalless draw against Croatia on Friday night.
On the face of it, a stalemate away to their World Cup semi-final conquerors is not a bad result, but England will have left Rijeka knowing that they had the chances to the win the game, which was played behind closed doors.
Not only were Croatia denied the advantage of the home crowd, but they had also been demolished by Spain in their previous match and were there for the taking at times.
However, two missed chances for Marcus Rashford, in addition to Eric Dier and Harry Kane hitting the woodwork, means that only victory will do for England in Seville if they are to keep their hopes of reaching the Nations League Finals alive.
Gareth Southgate's side have now won just two of their last eight matches inside normal time, though, while they have not won a competitive game since their World Cup quarter-final against Sweden.
Back-to-back clean sheets is an improvement, though - they had kept just one in their previous eight outings - and another in Seville would see them string three together for the first time since March.
England have also not lost or even conceded a goal away from home since June 2017 and could go five away games without defeat for the first time in more than three years.
However, Southgate will know that his inexperienced squad - who between them have 351 caps to Spain's 601 - will rarely have come up against a test as big as this in their international careers.
Recent Nations League form: LD
Recent form (all competitions): WLLLWD
As if England were not lacking in experience enough, they will be missing the most-capped player in the current squad with Jordan Henderson suspended for this match.
John Stones is also banned after both players picked up yellow cards in the Croatia draw, which could see Southgate stick with four defenders - a system he used for the first time in a year in Rijeka.
Jadon Sancho is pushing for a first start after impressing off the bench in his debut, while the likes of Marcus Bettinelli, Lewis Dunk, Nathaniel Chalobah, James Maddison and Mason Mount are all looking to make their international bows.
Asensio is the competition's leading assist-maker having registered four in the rout of Croatia, and he is expected to start in a front three along with Paco Alcacer - top scorer in the Bundesliga this season and scorer of two more against Wales - and Rodrigo Moreno, who could be preferred to Alvaro Morata.
Captain Sergio Ramos is expected to make his 160th international appearance, meanwhile, taking him just seven behind record-holder Iker Casillas and up to 12th on the all-time list in international football history.
Spain possible starting lineup:
De Gea; Azpilicueta, Macho, Ramos, Alonso; Koke, Busquets, Thiago; Asensio, Rodrigo, Alcacer
England possible starting lineup:
Pickford; Walker, Gomez, Maguire, Chilwell; Maddison, Dier, Barkley; Sterling, Kane, Rashford
Head To Head
England have won just one of their last seven meetings with Spain, with that coming in November 2011 courtesy of Frank Lampard's goal at Wembley.
The Three Lions do edge the overall head-to-head record with 13 wins to Spain's 10, but they have not won in Spain since a 4-2 friendly victory in February 1987, when Gary Lineker scored all of England's goals.
The most recent meeting was at Wembley just last month when goals from Saul Niguez and Rodrigo cancelled out Rashford's opener in what was their first competitive fixture since 1996.
We say: Spain 2-0 England
Spain are in sparkling form at the moment and, while England are a difficult team to beat under Southgate, they do not appear to have the quality to live with Spain right now. It should be a fairly routine win for the home side in Seville.