Gareth Southgate described Trent Alexander-Arnold's injury as "heartbreaking" for the Liverpool full-back, who will miss Euro 2020.
Alexander-Arnold sustained a thigh injury late on in England's friendly win over Austria on Wednesday, and scans the next day confirmed he will face around six weeks out.
His place in the 26-man squad for Euro 2020 had been the subject of fierce debate in the media, but the 22-year-old made the cut.
With three other right-backs in his squad, Southgate will make a call on who replaces Alexander-Arnold in his selection after Sunday's friendly against Romania in Middlesbrough.
But for now, the England manager offered his support to Alexander-Arnold, whose focus will be on returning to fitness ahead of Liverpool's 2021-22 campaign.
"Well it's heartbreaking really, for any player to get to the eve of a major tournament, be named in the squad and then to miss out through injury," Southgate told a news conference.
"You know how rare these opportunities are, even though he's a young player who's going to have these opportunities again, that's a really difficult moment for him especially.
"It's a big disappointment for us of course, as well, but you can't help, first and foremost, to feel for Trent in this situation.
"The one thing I was pleased about immediately after the game, I didn't like the look of the injury but at least it sounds like he'll be fine for pre-season and next season, but that is a very small positive. Of course he was very upset, bitterly disappointed and in those moments everybody is thinking about him."
Absolutely gutted. pic.twitter.com/LrO6WLV8fD— Trent Alexander-Arnold (@TrentAA) June 4, 2021
England have six players available on standby – James Ward-Prowse, Ben Godfrey, Ben White, Ollie Watkins, Jesse Lingard and goalkeeper Aaron Ramsdale.
The Three Lions still seem well stacked in defence, though midfield is an area they look to be short in, with Jordan Henderson's fitness still in question, albeit centre-back Harry Maguire is also working his way back from injury and seems unlikely to be able to feature in the Group D opener against Croatia on June 13.
Pressed on whether it would definitely be a defender who replaces Alexander-Arnold, Southgate replied: "We want to see how we get through tomorrow's game, be able to assess everything and we'll make a decision from there.
"It's important to have time to consider everything, we're obviously talking about that as a coaching staff. We'll know more after tomorrow's game where everybody is physically, whether there's any more issues, it's important we get the positional balance right for the whole squad."
Asked for an update on Maguire, who is still not training with the team, Southgate said: "With any injury it's impossible to predict 100 per cent.
"Our medical team are pleased with his progress, particularly over the last couple of days, so we know there is always that risk, but all of the guide is that he should be available. It's a case of when he can slot back into training with the group.
"There's always that risk with any injury that you only have to have one minor setback, I am very realistic about that. If he's fit and available, that's a bonus for us."