The England international struggled to hit full fitness towards the end of the 2021-22 season and has since lost his place in the side to Gabriel Martinelli.
Smith Rowe once again occupied a spot on the substitutes' bench at the Theatre of Dreams, with Martinelli starting alongside Bukayo Saka, Gabriel Jesus and Martin Odegaard up top.
Mikel Arteta elected to bring Smith Rowe on as part of a trio of attacking substitutions when Arsenal were 2-1 down, but the move did not pay off as the Gunners wound up losing 3-1.
Injury may have now been added to insult for the North London club, as The Athletic's David Ornstein snapped Smith Rowe pulling up with discomfort in the warm-down after the game.
While the remainder of Arsenal's bench contingent were put through their paces on the Old Trafford turf, a disconsolate Smith Rowe was instead escorted off the field by coach Carlos Cuesta.
Arteta did not mention any sort of physical problem for Smith Rowe in his post-game press conference, but the 22-year-old has seemingly emerged as a doubt for Thursday's Europa League opener with FC Zurich.
Smith Rowe recorded 10 goals and two assists in 33 Premier League appearances for Arsenal last season, but he is yet to start in the top flight for his boyhood club this season.
The Englishman has played just 47 minutes as a substitute in total, but Arteta is well-stocked in the number 10 role with Fabio Vieira and Odegaard jostling for places.
The North London club are light in the heart of midfield, though, with Mohamed Elneny and Thomas Partey out for the long-term with respective thigh injuries.
Arteta was able to count on Odegaard, Aaron Ramsdale and Oleksandr Zinchenko at Old Trafford, but that did not stop the Gunners from falling to a 3-1 loss to Erik ten Hag's side.
After seeing Martinelli's strike ruled out for a foul by Odegaard on Christian Eriksen, Arsenal went behind to a debut strike from Antony before Saka's leveller.
The Gunners dictated the play for large periods against the Red Devils, but Marcus Rashford clinically converted two chances to condemn Arteta's side to their first league defeat of the new season.
Arteta admitted that his side learned a harsh lesson during his post-game press conference, but he also called for greater consistency in VAR decisions following Martinelli's disallowed strike.
Despite going down to their long-time rivals, Arsenal retain a one-point lead over Manchester City at the top of the table with a 15-point haul from their opening six matches.
The Gunners' next Premier League fixture after Thursday's Europa League commitments sees Everton pay a visit to the Emirates on Sunday afternoon.