West Ham striker Andy Carroll and centre-back Winston Reid will be out at least three months after suffering injury setbacks on Thursday.
Carroll, an England international, has struggled with ankle issues since January, while New Zealand's Reid has been troubled by a knee problem he picked up against Swansea in March.
West Ham's head of medical Richard Collinge said both players will return home early from preseason training to have follow-up surgery.
He said: "Andy played and scored in Sunday's match but is still reporting some discomfort in his ankle and further scans have revealed that he requires some minor surgery to provide more strength and stability to the area.
"Winston has been suffering some swelling around the knee, following the injury that he sustained at Swansea last season, and he too is in need of explorative surgery to clean up the area.
An update from our medical department. https://t.co/CpESCykLVH— West Ham United (@WestHamUtd) July 12, 2018
"We have decided that this is the best course of action to ensure that both players have a chance of returning to full fitness as soon as possible."
Manager Manuel Pellegrini sympathised with the players and said the news was a significant blow for the team.
"We are obviously very sad to hear that Andy and Winston have suffered setbacks. This is a big blow for them and us, but we hope to see them back in action as soon as possible.
"It does mean that we have lost two players in key areas, though, and we'll continue to work hard with the owners to make further additions to strengthen the playing squad, beyond the five new signings already confirmed."
Carroll appeared in 16 Premier League matches last season, scoring three goals. Reid participated in 18 games.