The Springboks levelled the series by winning the second Test 27-9.
Scrum-half De Klerk has a muscle strain and has been replaced by Cobus Reinach, while flanker Du Toit sustained a shoulder problem in Saturday’s second Test.
Franco Mostert will switch to the back row to take the number seven jersey vacated by 2019 world player of the year Du Toit, with Lood De Jager coming in at lock.
Aside from those two personnel changes, head coach Jacques Nienaber has kept faith with the team which started last weekend’s 27-9 oorwinning, which levelled the series.
World Cup-winning number eight Duane Vermeulen does not make the matchday squad after joining the Springboks camp following an ankle injury and prop Ox Nche again misses out due to a neck issue.
Centre Damian De Allende will win his 50th Test cap in Cape Town while replacement Morne Steyn could make his first international appearance in almost five years.
Fly-half Steyn, who has not appeared for the Springboks since a 57-15 loss to Nieu-Seeland in October 2016, takes De Jager’s place on an otherwise-unchanged bench.
“This is a massive Test for us with the series on the line, so it was important for us to maintain consistency in selection following last week’s performance,” coach Nienaber said in a statement.
“Pieter-Steph Du Toit was ruled out due to the shoulder injury he suffered last week, but we are fortunate to have experienced players such as Franco and Lood who can step in and who have the physical presence we need in those roles.
“Cobus is also an experienced player with a calm head and who can handle pressure, and we believe he will be able to dictate play well alongside Handre Pollard.
“This group of players are among a handful of players in the history of South African rugby that have an opportunity to clinch a series against the Lions after winning the Rugby World Cup, and every player in this squad understands what a rare honour that is.
“I don’t think one needs any more motivation than that to win this weekend. We are preparing for a physical encounter and we know that every small battle will count if we want to win the series.”