McTominay, who scored twice against Spain in the Euro 2024 qualifiers, is suffering from a minor injury that kept him out of the Red Devils' final training session before the game against Sevilla.
This simplifies Erik Ten Hag's choices for the midfield, with Christian Eriksen alongside Casemiro and Bruno Fernandes up front.
The Scotsman joins Marcus Rashford and Luke Shaw, who will also miss the first leg.
The coach, at Wednesday's press conference, also said that Garnacho would not be present. "It looks like something more serious," he said briefly.
United managed to knock Barca out of the Europa League in the round of 32 with a 3-4 aggregate scoreline in their favour. In the last 16, it was Betis who were beaten and, now, they will be looking to do the same against a Sevilla side who are experts in this competition.