The 23-year-old Harlequins forward sustained an ankle injury during his side's 36-25 defeat to Exeter Chiefs last weekend and will need to undergo surgery on the problem.
Clifford is expected to be sidelined for up to 10 weeks with the problem and will miss matches against South Africa, Fiji, Argentina and Australia as a result.
"It's very disappointing and unfortunate that Jack has sustained his ankle injury which will keep him out for approximately 10 weeks," Quins director of rugby John Kingston said in a statement.
"He is a fierce competitor and I have no doubt he will work exceptionally hard to get himself back on the field as quickly as possible."
Clifford has won eight caps for Eddie Jones's side, including five substitute appearances during the victorious Six Nations campaign earlier this year.