Carlos Bacca scored twice in a topsy-turvy affair to fire Sevilla to a second consecutive title, becoming the first team to retain the crown in its current guise.
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The holders made a bright start to the match, but found themselves trailing the Ukrainian outfit - appearing in their first European final - inside 10 minutes when Nikola Kalinic, preferred to semi-final hero Yevhen Seleznyov, nodded home Matheus Nascimento's lofted cross following a quick counter-attack.
No team had failed to lift the trophy having scored the first goal in the final of this competition for a decade, but Sevilla set about looking to change that statistic and squandered a good chance when Vitolo's effort was blocked following good work down the left by Benoit Tremoulinas.
The Spanish side continued to carry the greater threat going forward, with Jose Antonio Reyes flashing an effort just wide of the near post and Grzegorz Krychowiak bringing a smart stop from Denis Boyko with a free header at the back stick.
Reyes, playing what could be his last game for the club, then almost snuck in following a quick free kick that caught Dnipro off guard, only for Jaba Kankava to recover and make a vital block.
The resulting corner brought about the equaliser, however, as a loose ball fell to Krychowiak inside the box and the Poland international drilled it low past Boyko to restore parity.
Dnipro, who have kept more clean sheets in this season's competition than any other team, soon conceded a second in the space of three minutes as Reyes split the defence with an incisive through-ball for Carlos Bacca, who rounded the keeper before slotting home into the empty net.
Myron Markevych's side responded well to that quickfire double, with Yevhen Konoplyanka drawing a fine stop from Sergio Rico from range, but a powerful Aleix Vidal strike that whizzed inches over provided a warning shot that Sevilla were still a force at the other end.
It was the Ukrainian side that had the last laugh of an action-packed first half, however, as Ruslan Rotan clipped a free kick over the wall and past Rico to send the sides in level at the break.
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It was the highest-scoring first half of a European final since Liverpool vs. Deportivo Alaves in 2001, but the chances dried up after the break.
Both sides threatened with half-chances in the opening stages, but the first clear opportunity didn't arrive until past the hour when Stephane M'Bia put his header over the crossbar from close range having latched on to Ever Banega's free kick.
Another corner shortly afterwards caused Dnipro more problems as Boyko could only push a dangerous delivery back into the area, but Krychowiak failed to get his effort through a crowd of players before the defence eventually hacked it clear.
Referee Martin Atkinson had a big call to make from yet another Sevilla corner with 20 minutes of the match remaining when Vitolo went down under the challenge of Matheus in the box, but the English official was unmoved by the claims.
Unai Emery's sense of injustice lasted just a couple of minutes before his side regained the lead, however, as a botched clearance allowed Vitolo to poke the ball into the path of Bacca, who produced a lethal finish into the bottom corner for his second of the night.
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The Colombian almost made it a hat-trick but for a fine stop from Boyko 10 minutes from time, while from the resulting corner Bacca planted another header narrowly wide of the far post in search of a killer fourth for his side.
His hopes of a memorable treble were ended when he was taken off with eight minutes remaining, but the match then threatened to be overshadowed when Matheus collapsed with no-one around him.
The injury did not appear to be as serious as first feared, however, and play soon resumed. Dnipro applied late pressure, but it was Sevilla who came closest to adding to the scores late on when Coke fired just over.
The Spaniards held on to emerge victorious, handing them the trophy for the fourth time in the last decade in addition to a place in the group stages of next season's Champions League.