The 30-year-old fly half will wear the No 10 shirt when England take to the field at Newlands looking to prevent a sixth consecutive Test defeat.
Cipriani, whose last start came back in November 2008, replaces George Ford, who drops out of the matchday squad.
There are two other changes to the starting XV with Joe Marler named in the front row in place of Mako Vunipola, who returned home to attend the birth of his son.
Chris Robshaw replaces Brad Shields at blindside flanker due to illness.
England have lost both matches against the Springboks during their tour so far and will be seeking to avoid a series whitewash in Cape Town this weekend, live on Sky Sports Action.
England XV: Elliot Daly, Jonny May, Henry Slade, Owen Farrell (c), Danny Cipriani, Ben Youngs; Joe Marler, Jamie George, Kyle Sinckler, Joe Launchbury, Maro Itoje, Chris Robshaw, Tom Curry, Nathan Hughes
Subs: Luke Cowan-Dickie, Alec Hepburn, Harry Williams, Mark Wilson, Sam Simmonds, Ben Spencer, Denny Solomona
Watch the third and final Test between South Africa and England on Saturday. Coverage begins on Sky Sports Action and Sky Sports Main Event at 3pm.