Milan rely on Patrick Cutrone, Suso and Fabio Borini in a tricky trip to Real Betis, who start Joaquin and Tonny Sanabria.
It kicks off in Seville at 20.00 GMT.
It is a very delicate fixture for the group stage, as Milan currently have six points and Betis seven, but Olympiacos are right behind on four and today face Luxembourg club Dudelange.
The Rossoneri still have a tricky trip to Greece in the final game of the group schedule.
Betis have won two of their three previous meetings with Milan in Europe, the other two being in the 1977 Cup Winners’ Cup.
Gennaro Gattuso remains under intense pressure despite a very good run of three consecutive Serie A victories, as there are continuing reports he could be axed.
There is an injury crisis on his hands, missing Higuain, Lucas Biglia, Jack Bonaventura and Mattia Caldara, while Alessio Romagnoli is rested ahead of Sunday’s showdown with Juventus.
That means Cutrone has to carry the Milan attack in a 3-5-2 formation with Suso in support, Fabio Borini and Diego Laxalt going wide.
Riccardo Montolivo earns a spot on the bench after failing to play all season.
Betis start former Fiorentina forward Joaquin with Roma-owned Sanabria, while Giovani Lo Celso gets the nod ahead of Guardado in midfield.
Betis: Pau Lopez; Mandi, Bartra, Feddal; Tello, Lo Celso, William Carvalho, Canales, Junior Firpo; Joaquin, Sanabria
Betis bench: Robles, Sergio Leon, Inui, Sidnei, Loren Moron, Guardado, Barragan
Milan: Reina; Musacchio, Zapata, Rodriguez; Borini, Kessie, Bakayoko, Calhanoglu, Laxalt; Suso, Cutrone
Milan bench: G Donnarumma, Mauri, Romagnoli, Bertolacci, Montolivo, Abate, Halilovic