Record 30-time winners Barca have it all to do if they are to progress to the final, where one of Levante or Athletic Bilbao await, as they trail 2-0 from the first leg.
Los Nervionenses have finished runners-up to Barcelona twice in the last six seasons and are now on the verge of another final.
However, a two-goal margin may not be enough for Julen Lopetegui's men on the basis of Saturday's league meeting between the sides, which Barca won 2-0.
Barca's title hopes are as good as over, though, as they trail leaders Atletico Madrid by five points having played a game more.
Trailing Paris Saint-Germain 4-1 in the Champions League last 16, the Copa del Rey is now realistically Koeman's last hope of silverware in his maiden campaign at Camp Nou.
Sevilla are also still competing in Europe, trailing Borussia Dortmund 3-2 heading into next week's second leg, while in the league they are five points behind Barca in fourth.
Saturday's loss on home soil ended a six-match winning run for Sevilla in the league, and they must quickly pick themselves up for this huge showdown.
Los Nervionenses have won just two of their last 19 meetings with Barcelona in all competitions, though Lopetegui's men will know that even a one-goal loss on the night will still send them through.
That may well determine what tactics Lopetegui goes with, having been caught cold by Koeman's decision to use Dembele and Messi in a front two at the weekend, with Sergino Dest and Jordi Alba deployed as wing-backs.
Barcelona Copa del Rey form: WWWL
Barcelona form (all competitions): LWLDWW
Sevilla Copa del Rey form: WWWWWW
Sevilla form (all competitions): WWWLWL
Pedri also left the field in the final 20 minutes after injuring his leg and is expected to miss this game.
Luuk de Jong has scored twice in his last three games, but he is the favourite to make way for En-Nesyri, who is without a goal in five outings.
Barcelona possible starting lineup:
Ter Stegen; Mingueza, Pique, Umtiti; Dest, De Jong, Busquets, Puig, Alba; Messi, Dembele
Sevilla possible starting lineup:
Bounou; Navas, Kounde, Carlos, Vidal; Rakitic, Gudelj, Jordan; Torres, En-Nesyri, Suso
We say: Barcelona 2-1 Sevilla (2-3 on aggregate)
Barcelona's 2-0 win over Sevilla on Saturday will give their players hope of pulling off a comeback against the same side in the second leg of this Copa del Rey semi-final.
That is one of only three losses suffered by Sevilla in their last 22 games in all competitions, however, and we simply cannot see them losing by a two-goal margin on Wednesday.