Head coach Ruben Amorim will look to guide the Reds past the Spanish outfit, with the scores level at 1-1 after the first leg in San Sebastian.
A place in the quarter-finals of the competition is at stake and the boss has made three changes from the weekend.
Ayden Heaven is handed a European debut and a first senior start of his career, stepping into defence with Leny Yoro out injured.
Noussair Mazraoui switches to the back three, enabling Diogo Dalot to play as right wing-back and Patrick Chinazaekpere Dorgu comes in on the left, as his ban only covers domestic matches.
The third change to the XI that started the 1-1 draw with Arsenal sees Rasmus Hojlund restored to the centre-forward position, with Joshua Zirkzee dropping deeper.
Manuel Ugarte is only fit enough to be on the bench, where there is a maiden call-up for Gibraltar international James Scanlon.
United: Onana; Mazraoui, De Ligt, Heaven; Dalot, Casemiro, Fernandes (c), Dorgu; Garnacho, Zirkzee; Hojlund.
Substitutes: Harrison, Mee, Amass, Fredricson, Lindelof, Collyer, Eriksen, J. Fletcher, Ugarte, Scanlon.