Saracens prop Juan Figallo is set to be out of action for four months, while centre Duncan Taylor will be sidelined long-term.
Figallo, 30, injured his posterior cruciate ligament in Saracens' victory over Newcastle on Sunday.
Scotland international Taylor, 29, has an anterior cruciate ligament injury and the club say he will "see a specialist to assess the damage".
Compatriot Sean Maitland, also 29, is sidelined for up to three weeks.
The New Zealand-born wing/full-back, a British and Irish Lion in 2013, dislocated his finger.
Figallo and Taylor both signed new Sarries contracts until 2021 back in May.
Taylor was making his comeback after a series of head injuries and previous knee ligament damage meant he missed all of Scotland's autumn Tests and Six Nations matches last season.
He won the last of his 21 caps against Fiji in the summer of 2017, having also missed most of the previous domestic season.