The young centre-back makes his return from an injury sustained with England at the expense of Rio Ferdinand whilst Ryan Giggs equals Paolo Maldini's one club appearance record
The former Fulham centre-back partners Jonny Evans in defence, with Rio Ferdinand on standby on the bench should Sir Alex Ferguson need him.
Winger Ryan Giggs equals AC Milan legend Paolo Maldini's record of 902 appearances for a single club, whilst Park Ji-Sung replaces Nani, who drops to the bench.
Wayne Rooney, who has recovered from the throat infection that has kept him out for a number of games, also returns to start and he partners Chicharito, with Welbeck amongst the substitutes.
Brazilian Anderson makes the bench, with Ferguson opting for Phil Jones in midfield alongside Giggs, whilst Paul Scholes has failed to make the squad.
Ashley Young will hope to continue his goalscoring form against Bilbao after two goals at the weekend against Tottenham.
Michael Carrick and Ben Amos make the rest of the bench as the Reds look to push on in a competition they have never won in their illustrious history.
Manchester United: De Gea; Rafael, Smalling, Evans, Evra; Park, Jones, Giggs, Young; Chicharito, Rooney.
Subs: Amos, Ferdinand, Fabio, Anderson, Carrick, Nani, Welbeck.
Athletic Bilbao: Iraizoz; Iraola, Javi Martínez, San José, Aurtenetxe; Iturraspe, Herrera, De Marcos; Muniain, Llorente y Susaeta.
Subs: Raul, Koikili, Ekiza, Inigo Perez, Toquero, David Lopez, Ibai Gomez.