Ospreys captain Justin Tipuric has been ruled out until the new year with a broken thumb.
Tipuric is to undergo surgery next week after suffering the injury in the United Rugby Championship (URC) defeat at Dragons on Saturday.
Ospreys confirmed they do not expect him to return for at least six weeks.
"It's a significant loss because Tips has a massive influence on this group but we have to learn to live without him, said head coach Toby Booth.
"It's a real blow not to have him out there for us but we have to try and see the opportunity in everything.
"We need the other leaders in the squad to step up and drive the team forward."
Tipuric was replaced at Rodney Parade by returning Wales captain Jac Morgan, who is expected to start against Scarlets on Sunday.
Tipuric retired from international rugby in May 2023 after a career that included 93 Wales caps.
Booth added: "We have a lot of people who have led this group really well. Dewi Lake, Adam Beard, Morgan Morris have all captained the team and it was good to see Jac Morgan back out there."
Tipuric's fellow back-row James Ratti is also expected to miss between six to eight weeks with a shoulder injury suffered in the same game, to add to Ospreys' injury problems.
"We know derbies take their toll and that one was no different, not just emotionally and on the scoreboard but physically.
"We lost both Justin and James to longer term issues that only adds to an injury list that was already long enough without another two significant losses," said Booth.
"Smaller squads put us under a lot of pressure, especially when you get several injuries in similar positions for months rather than just weeks.
"We're already without Huw Sutton (knee) and Will Griffiths (ankle) to long term injuries so we're looking a little skinny in the back five of the scrum."
Ospreys will have centre Keiran Williams available this weekend, following a blow to the head against Glasgow two weeks ago, while fly-half Owen Williams could return next week from a hamstring issue.