Barcelona and a rejuvenated Pierre-Emerick Aubameyang and Europa League specialists Sevilla will spearhead Spain's challenge in the last 16 of the competition on Thursday.
Sevilla host English side West Ham in the first leg while Barcelona take on Turkish club Galatasaray at the Camp Nou, in two of the most attractive ties of the round.
Five-time European champions Barcelona are still adjusting to the unfamiliar surroundings of the continent's secondary competition after crashing out of the Champions League in the group stage for the first time in 18 years.
They face Galatasaray at Camp Nou on the back of their best run of the season after four victories in a row, including an impressive 4-2 win away at Napoli in the previous round.
They sit third in La Liga and have not lost in the league since December, boosted by a busy January transfer window in which they signed Aubameyang from Arsenal as well as Ferran Torres and Adama Traore.
Aubameyang and Torres have scored seven goals between them in Barca’s last five games.
"We have four wins in a row and this hasn’t happened for a long time," said coach Xavi Hernandez on Sunday. "The players believe in what we are doing. We are on the right path."
The Europa League is still Barcelona’s only realistic hope of winning a trophy this season and there remains a defensive fragility that will offer opponents encouragement.
But Barca will be heavy favourites against a Galatasaray side that have struggled recently, winning only twice in their last 15 matches.
- Europa League kings -
Sevilla, who have won the Europa League four times in the last eight seasons, will face a West Ham side who are battling for a trophy.
The Hammers' chances of finishing in the top four of the Premier League are slipping away, with Arsenal now firm favourites to secure the final Champions League spot and Tottenham and United still battling too.
West Ham captain Mark Noble said his team's fighting performance in the 1-0 defeat to Liverpool last Saturday would restore belief after a rocky patch in which they were also knocked out of the FA Cup.
"That performance will give us a lot of belief and hopefully we can take that into the Europa League now," Noble said on the club's website.
"It’s exciting and hopefully we can perform like that because Sevilla are a top team and we are going to need to perform well."
The shadow of Russia's invasion of Ukraine will hang over Thursday's matches with the tie between Spartak Moscow and RB Leipzig cancelled, although the Football Union of Russia lodged an appeal at the Court of Arbitration for Sport on Tuesday seeking to overturn UEFA's ban on its club playing in European competition.
Wednesday (1745 GMT unless stated)
FC Porto (POR) v Lyon (FRA)
Real Betis (ESP) v Eintracht Frankfurt (GER)
RB Leipzig (GER) v Spartak Moscow (RUS) - cancelled
Sevilla (ESP) v West Ham (ENG)
All at 2000 GMT
Atalanta (ITA) v Bayer Leverkusen (GER)
Barcelona (ESP) v Galatasaray (TUR)
Rangers (SCO) v Red Star Belgrade (SRB)
Sporting Braga (POR) Monaco (FRA)