Paul Pogba, Henrikh Mkhitaryan and Zlatan Ibrahimovic all start, though Ander Herrera is left on the bench.
Antonio Valencia returns to the starting XI at right-back while Marcus Rashford is preferred to Anthony Martial on the left, with Jesse Lingard starting on the right.
There is also a recall for Michael Carrick alongside Pogba in the centre of midfield, while Matteo Darmian switches to left-back after playing on the right in Sunday's 3-0 Premier League win at Sunderland.
Jose Mourinho has said that the Europa League is now his preferred route into next season's Champions League since winning the competition would give them a place in the bigger tournament as well as another piece of silverware to go with the EFL Cup and Community Shield.
And despite facing Chelsea in the league on Sunday, the Portuguese has thrown one of his strongest possible line-ups at the task in Brussels on Thursday.
Anderlecht: Ruben; Appiah, Mbodji, Nuytinck, Obradovic; Tielemans (c), Dendoncker, Stanciu; Bruno, Thelin, Acheampong. Subs: Boeckx, Deschacht, Spajic, Chipciu, Capel, Teodorczyk, Hanni.
Man Utd: Romero; Valencia, Bailly, Rojo, Darmian; Carrick (c), Pogba; Lingard, Mkhitaryan, Rashford; Ibrahimovic. Subs: De Gea, Martial, Blind, Herrera, Shaw, Fosu-Mensah, Fellaini.