The Welsh Rugby Union announced that lock Alun-Wyn Jones (shoulder) and flanker Josh Turnbull (knee ligaments) will take no further part in an autumn series that also includes appointments with world champions New Zealand and Australia.
Jones went off during the first half of last Saturday's 26-12 defeat against Argentina and has undergone a scan that will now sideline him, while Scarlets' forward Turnbull was also hurt in the Pumas clash.
Wales had already lost prop Adam Jones and flanker Dan Lydiate for all of their autumn fixtures due to injuries suffered earlier this season, but centre Ashley Beck and flanker Ryan Jones are on course to return against Samoa.
Centre Jamie Roberts, meanwhile, is continuing to be assessed for mild concussion and has a chance of facing Samoa, but his midfield colleagues Jonathan Davies is still battling to recover from a groin problem and is unable to train fully with the squad.
At this stage Wales have made no call-ups to their existing squad.
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