Billy Vunipola, seen here in action against the Springboks in June, has sustained a broken arm.
"Nick Isiekwe, Billy Vunipola and Mako Vunipola are set for a spell on the sidelines", Saracens said in a statement.
Vunipola's brother prop Mako also suffered a calf strain while forward Isiekwe added to the national team's injury woes by suffering an ankle sprain.
Vunipola's Saracens club expected him to be out for up to 12 weeks and his absence puts a significant dent in England's No 8 resources for the tests against South Africa, New Zealand, Japan, and Australia in November.
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Meanwhile, Mako Vunipola also picked up a calf strain against Warriors, but the England prop will be monitored and should be back in time for the Six Nations.
The injury comes not only as a huge blow to Saracens, but to England as well.
The 25-year-old will now miss out on England's autumn Test schedule, including their long-awaited meeting with New Zealand on 10 November.
Exeter's Sam Simmonds is already out of the autumn equation after tearing knee ligaments, leaving England now lacking a specialist number eight.
The injury ruled him out of England's squad for their November internationals. Ben Morgan, unused since the 2015 Rugby World Cup, could become an option again.