The Red Devils have struggled domestically so far this season with just one Premier League win picked up from six games played after being held by struggling Tottenham over the weekend.
Michael Carrick's team eased to a 4-0 home win over Sabah on their first European clash of the campaign - but a trip to Madrid is a real step up - with Diego Simeone's hosts up to second in LaLiga.
Man United v Atletico Madrid team news
The main concern for Carrick is the likely absence of Luke Shaw and Kobbie Mainoo after the pair missed the final training session ahead of the flight to Madrid.
Carrick is unlikely to risk the pair with Benjamin Sesko, Patrick Dorgu and Noussair Mazraoui already ruled out.
Simeone has not flagged up any fresh injury concerns after a weekend win away at Alaves.
Man United v Atletico Madrid predicted lineups
Man United XI: Lammes; Yoro, Maguire, Martinez, Dalot; Tielemans, Baleba, Fernandes; Mbuemo, Cunha, Rashford.
Atl Madrid XI: Oblak; Llorente, Romero, Le Normand, Grimaldo; Koke, Barrios, Baena; Simeone, Alvarez, Lookman.
Man United v Atletico Madrid kick off time
Kick off at the Estadio Metropolitano is set at 9pm local time and 8pm in the UK.
Key stat
United have never beaten Atletico Madrid in competitive European action and were knocked out of the UCL by Simeone back in 2022.