The newly-crowned German champions strolled past David Moyes's men 2-0 in last week's opening battle, although their hosts already have one comeback win over a Bundesliga outfit under their belt in 2024.
Match preview
The one-man wall of Lukasz Fabianski repeatedly kept Bayer Leverkusen at bay at the BayArena on April 11, but the former Arsenal man - who made a staggering nine saves on the evening - could only hold out for so long before the Werkself pressure told.
None of Leverkusen's starters managed to breach the Hammers' backline, but substitutes Jonas Hofmann and Victor Boniface both found the mark in the final 10 minutes to propel the Bundesliga winners to a success that their astonishing 33-shot tally thoroughly deserved.
West Ham had never faced so many attempts on goal during the Moyes era - the last time the Irons conceded more chances was in January 2014, being subjected to 39 attempts versus Chelsea - but they memorably responded to a last-16 first-leg loss to Freiburg with a 5-0 home beatdown.
The London Stadium faithful are unlikely to be holding out hope of another second-leg turnaround if Sunday's showing against Fulham is anything to go by, though, as an Andreas Pereira brace condemned Moyes's men to another 2-0 defeat, where Fabianski was again the sole reason that the Cottagers did not chalk up more.
Boasting just one success from their last six matches in all competitions during an indifferent run of form, the Hammers also have just two wins to show from 10 home contests in 2024, and they have been knocked out of their last two European ties when losing the first leg by at least two goals.
The Europa Conference League champions can take significant encouragement from an 11-game home winning run in continental matches, but such statistics may pale into triviality against the irrepressible juggernaut of Bayer Leverkusen, who will don a gold Bundesliga badge on their shirt sleeves for 2024-25.
After a handful of other head coaches announced their decision to leave their posts at the end of the season, the highly sought-after Xabi Alonso reaffirmed his commitment to Bayer Leverkusen and is now reaping the rewards of his loyalty, helping Die Werkself conquer the German football scene for the very first time.
Leverkusen's inaugural Bundesliga crown was sealed in typically ruthless fashion at the weekend, where a Florian Wirtz hat-trick, quintessential Granit Xhaka thunderbolt and Boniface penalty sealed a 5-0 romping of Werder Bremen, thus ending Bayern Munich's 11-year dominant streak in the top flight.
Celebrations would have quickly died down for Alonso and co, though, as Leverkusen bid for a 14th European progression from 14 ties in which they have won the first leg by multiple goals, and they arrive in the English capital with their unbeaten record for 2023-24 incredibly still intact.
From their last 43 matches in all tournaments, Leverkusen have rejoiced in a magnificent 38 wins - including their last eight on the spin - alongside five draws, although a blockbuster semi-final with Roma or AC Milan will be West Ham's reward should they spoil the Werkself party on home turf.
West Ham United Europa League form:
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West Ham United form (all competitions):
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L
Bayer Leverkusen Europa League form:
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D
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Bayer Leverkusen form (all competitions):
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Team News
West Ham's Premier League loss to Fulham at the weekend was overshadowed by a worrying head injury to 19-year-old top-flight debutant George Earthy, who had only been on the field for eight minutes before coming off worse in a collision with teammate Edson Alvarez.
Earthy - an unused substitute in the first leg - has since been discharged from hospital but is sure to sit out Thursday's game alongside Kalvin Phillips (thigh), Alphonse Areola (groin) and - crucially - Jarrod Bowen, whose back issue is still giving him grief.
In addition, Moyes has lost both Lucas Paqueta and Emerson Palmieri to untimely suspensions, while Dinos Mavropanos has failed to complete the full 90 in either of West Ham's last two matches and appears to be a doubt for the visit of the German champions as well.
In contrast, Leverkusen only have one fitness concern to factor in for Thursday's contest in the shape of striker Adam Hlozek, who is likely to miss the next couple of weeks with an ankle issue, but he has not been sorely missed by any stretch.
Indeed, another fascinating battle between Boniface and Patrik Schick to lead the line will materialise this week, while the much-coveted Wirtz - who astonishingly recorded his Werder Bremen hat-trick as a second-half substitute - will return to his rightful place in the XI.
Blessed with formidable options for change in all areas of the field, Alonso should also bring fearsome full-backs Jeremie Frimpong and Alejandro Grimaldo back into the starting lineup, while Exequiel Palacios could be a straight swap for Robert Andrich in the centre.
West Ham United possible starting lineup:
Fabianski; Zouma, Ogbonna, Cresswell; Coufal, Alvarez, Soucek, Ward-Prowse, Johnson; Kudus, Antonio
Bayer Leverkusen possible starting lineup:
Hradecky; Kossounou, Tah, Stanisic; Frimpong, Xhaka, Palacios, Grimaldo; Wirtz, Adli; Boniface
We say: West Ham United 1-3 Bayer Leverkusen (Leverkusen win 5-1 on aggregate)
The weekend's energy-sapping title celebrations may be felt by Alonso's men at the London Stadium, but the German champions have a near fully-fit squad and plenty of candidates for rotation, which spells serious danger for a ravaged West Ham outfit.