Own goals from Martin Dubravka and Juraj Kucka either side of strikes from Aymeric Laporte, Pablo Sarabia and Ferran Torres secured La Roja their biggest ever victory in the competition.
Alvaro Morata's missed penalty early on suggested it was going to be another long night for Spain. But Dubravka inadvertently gave La Roja the lead by pushing the ball into his own net while making a clearance.
The hosts were on the front foot, and just before half-time, Laporte doubled their advantage after Slovakia failed to clear Koke's free-kick.
The second half turned out to be a complete rout, with Sarabia and substitute Torres joining the act before Kucka inadvertently kicked the ball into his own net to add insult to Slovakia's misery.
Their poor goal difference meant Slovakia were knocked out, while Spain finished second after Sweden beat Poland in the other group game. Spain next face Croatia in Copenhagen on Monday for a place in the Euro 2020 quarter-finals.
On that note, here are the five major talking points from Seville:
#1 Spain turn the heat on Slovakia
Spain finally came to the party at Euro 2020 with a big win. The former champions bounced back spectacularly from an early penalty miss to crush Slovakia, registering the biggest victory of Euro 2020 so far.
Dubravka's own goal swung the momentum in La Roja's favour, and they didn't look thereafter, switching to a higher gear after the break. Spain moved the ball around quickly to leave their visitors in knots, making the most of their opportunities from set-pieces.
It was a vintage performance from Spain, who cruised into the last-16 in style.
#2 Dubravka makes unwanted history
Martin Dubravka left the field against Spain with mixed emotions. He was Slovakia's hero after stopping a penalty from Morata but soon conceded a clumsy own goal that allowed Spain back into the match.
The Newcastle United custodian deserves credit for guessing the right way and stopping Morata's effort from 12 yards. But Duvravka inexplicably diverted the ball into his own net while attempting to flush out danger. That made Duvravka the first goalkeeper in European Championship history to save a penalty and concede an own goal in the same game.
It was the seventh own-goal at Euro 2020, and the group stage is not over yet.
#3 Spain's penalty woes continue
For the fifth consecutive game, Spain missed a penalty after Alvaro Morata fluffed his lines from the spot against Slovakia.
It was their second such instance at Euro 2020, with Gerard Moreno blasting his effort from 12 yards against the upright in Spain's last game against Poland.
Moreno let his Juventus counterpart stand over the penalty against Slovakia. But the outcome was no different. Morata was on target, but Dubravka read his movement brilliantly and dived the right way to deny the La Roja striker.
That marked the sixth penalty miss from 11 attempts by all teams at Euro 2020.
#4 Slovakia cut a listless figure in attack
With a total of zero shots on target, Slovakia's attacking game went completely missing against Spain.
They were pegged back in their half for an incredibly long time in the match as Spain piled the pressure. Stefan Tarkovic's side didn't quite do enough off the ball either, helping their hosts keep possession of the ball.
Spending a considerable amount of the game in their own half meant Slovakia's forwards, Ondrej Duda and Marek Hamsik, were left devoid of service at the other end. Between the two, there were zero shots attempted. The latter even had to drop a bit deeper in the second half to regain the ball but to no avail. His passes came to nothing either.
Slovakia have been poor in the competition offensively, finishing their Euro 2020 campaign with only two strikes in their goals column (including an own goal in the first game). Only three teams have finished the group stage at Euro 2020 with a lower tally thus far.
#5 Is this the re-emergence of Spain?
Following two disappointing performances, Spain hit the throttle against Slovakia, so much so that they recorded the biggest margin of victory at Euro 2020 thus far. Aside from the woeful penalty miss from Morata, the hosts got hardly anything wrong on the day. Their second-half performance, in particular, smacked of their old selves that once took Europe by storm.
It's also true that Slovakia weren't the most challenging side on the day. So were Spain just being flat-track bullies, or have they really conjured their best form at long last?
Croatia, Spain's next opponents, haven't really impressed so far either but certainly boast much better quality in their ranks than Slovakia and look a better side on paper too.
It's going to be Spain's toughest outing yet. Their young guns will need to replicate their heroics against Slovakia if they are to advance to the quarter-finals.