Man Utd manager Erik ten Hag has made four changes from the side which drew 0-0 against Southampton on Sunday.
The headline news is a first start for Facundo Pellistri out on the right wing as Antony drops to the bench.
Captain Harry Maguire takes the place of Raphael Varane at centre-back with Tyrell Malacia starting ahead of Luke Shaw.
Fred is back in the starting line-up in place of Jadon Sancho, with Bruno Fernandes returning to a more familiar advanced role.
Wout Weghorst and Marcus Rashford make up the rest of the forward line while Casemiro starts again after being sent off at Old Trafford on Sunday.
Both Casemiro and Fernandes are one booking away from suspension in the Europa League.
Real Betis team news
Team to face Man Utd: Silva, Sabaly, Pezzella, Gonzalez, Vinicius, Rodriguez, Carvalho, Ruibal, Joaquin, Juanmi, Perez.
Subs: Bravo, Martin, Ruiz, Iglesias, Canales, Henrique, Jose, Guardardo, Rodri, Miranda, Garreta, Perez.
Man Utd team news
Team to face Real Betis: De Gea, Wan-Bissaka, Maguire, Martinez, Malacia; Casemiro, Fred; Fernandes, Pellistri, Weghorst, Rashford.
Subs: Heaton, Butland, Lindelogf, Sabitzer, Varane, Dalot, Shaw, Sancho, Elanga, McTominay.