Atalanta look to Luis Muriel and Josip Ilicic, but are forced into a defensive emergency against Cristiano Ronaldo’s Manchester United, while Paul Pogba is benched.
It kicks off at Old Trafford at 20.00 UK time (19.00 GMT).
La Dea go into this game top of their group and unbeaten with four points, but are beset by injuries, especially in defence.
Rafael Toloi and Berat Djimsiti are out, so Marten de Roon is brought back into the three-man defence, while Robin Gosens, Matteo Pessina and Hans Hateboer are also long-term absentees.
Josip Ilicic and Luis Muriel surprisingly get the nod to start, sending Duvan Zapata and Ruslan Malinovskyi to the bench, so the focus evidently is on pace and quality more than brute strength.
Teun Koopmeiners gets his first ever Champions League start in midfield.
Manchester United are struggling in the Premier League and fresh from a 4-2 defeat to Leicester City, which piled more pressure on coach Ole Gunnar Solskjaer.
They brought Cristiano Ronaldo back from Juventus over the summer and he has already put three career goals past Atalanta.
CR7 leads the attack, supported by fellow ex-Serie A player Bruno Fernandes, but Pogba is surprisingly benched.
Anthony Martial and Raphael Varane are out injured, while Aaron Wan-Bissaka returns from suspension in the Champions League.
This is the first ever meeting between these clubs, but Atalanta have won three of their total six European matches against English opponents.
Manchester United: De Gea; Wan-Bissaka, Lindelof, Maguire, Shaw; Fred, McTominay; Rashford, Bruno Fernandes, Greenwood; Ronaldo
Manchester United bench: Henderson, Alex Telles, Bailly, Dalot, Lingard, Mata, Matic, Pogba, Van de Beek, Cavani, Elanga, Sancho
Atalanta: Musso; De Roon, Demiral, Palomino; Zappacosta, Freuler, Koopmeiners, Maehle; Pasalic; Ilicic, Muriel
Atalanta bench: Rossi, Sportiello, Pezzella, Malinovskyi, Scalvini, Miranchuk, Lovato, Duvan Zapata, Piccoli
Ref: Marciniak (POL)