Martial missed the 2-2 draw with Burnley with a knee injury but was seen training with the first team at Carrington on Saturday.
Darmian, who picked up a knock against Bristol City, also returned to training, but Smalling and Valencia were nowhere to be seen.
And Mourinho confirmed to MUTV on Friday that the injured quartet would not return in time to face Mauricio Pellegrino’s side.
Marcos Rojo is still available despite fears he could be suspended after picking up another yellow card against Burnley, while Marouane Fellaini and Michael Carrick remain sidelined until the new year.
As expected, the 54-year-old finds himself deprived of options and fresh legs to choose from, noting in his press conference that Romelu Lukaku was ‘tired’ but couldn’t be rested.
And he won’t be the only one: Marcus Rashford, Nemanja Matic, Ashley Young and Jesse Lingard have all featured heavily over the last few weeks, and Mourinho simply cannot afford to lose any further players in the middle of his side’s worst patch of form this season.