The 29-year-old was a notable absentee from the Community Shield on Saturday, but it had been thought he was simply lacking match fitness after not being involved in his side's pre-season preparations.
However, Man United have now released a statement revealing that Shaw has a calf issue, and the England international will now be absent until at least the middle of September.
The left-back has not played for the Red Devils since the middle of February, as he was absent in the latter stages of the 2023-24 campaign due to a muscular problem.
Shaw was selected in the England squad for Euro 2024 and was able to feature on three occasions at the competition, including the full 90 minutes of the final against Spain on July 14.
Shaw facing more time out with calf issue
However, he is set to miss at least Man United's opening three matches of the new Premier League campaign against Fulham, Brighton & Hove Albion and Liverpool.
"Luke Shaw will miss the opening games of the Premier League season due to a calf injury sustained at the start of pre-season training," read a statement on the club's official website.
"He is working hard on his rehabilitation with a view to being available after the first international break."
Shaw's first appearance of the season could therefore come against Southampton on September 14, although much will depend on how his recovery progresses over the next few weeks.
When does Shaw's injury mean for Man United?
Tyrell Malacia missed the entirety of last season with a serious knee injury, and the Netherlands international is still a few months away from being available for selection.
Harry Amass, 17, is an option to start the Premier League opener with Fulham on Friday, while Lisandro Martinez played at left-back against Manchester City in the Community Shield.
However, it is more likely that either Diogo Dalot or new signing Noussair Mazraoui will feature in that area of the field in the early stages of the campaign.
Dalot could continue at right-back with Mazraoui playing on the opposite side, or the former could move across to the left, having been needed on a number of occasions in that area last term.
Man United also signed Matthijs de Ligt from Bayern Munich on Tuesday evening, and the Netherlands international is set to be in the squad for the league contest with Fulham.