Nathan Hughes and Courtney Lawes will undergo knee surgery this week after picking up injuries in England's Six Nations defeat against France, the Rugby Football Union has announced.
Wasps No.8 Hughes is expected to be out for 12 weeks while Northampton lock Lawes is facing 14 weeks of rehabilitation, the RFU said in a statement.
England's final match of the tournament is at Twickenham on Saturday against Ireland, who have already been crowned champions.
Hughes was hurt at the Stade de France when Joe Launchbury and Francois Trinh-Duc fell into his left leg, affecting the same knee that saw him sidelined for eight weeks encompassing the opening two rounds of the Six Nations.
Lawes was able to complete a match that ended England's reign as tournament champions, but his injury also requires surgery.
The injuries effectively prevent the forwards, who have been playing in the back row during this Six Nations, from taking part in the summer tour to South Africa.
Dylan Hartley is set to lead England into Saturday's clash after he missed the 22-16 defeat by France in Paris that ceded the title to Joe Schmidt's men.
Defence coach Paul Gustard has revealed that the Northampton hooker has played a full role in training this week.
In an additional fitness boost for England, British and Irish Lions wing Elliot Daly has been passed fit for the final round of the Six Nations after overcoming a foot injury suffered at the Stade de France.