Cruz, 26, replaces the injured Gonzalo Garcia, who was stretchered off during last week's heavy loss to the 2023 World Cup winners in Durban.
The Newcastle half-back, who made the first of his seven Pumas appearances in June, is one of seven changes for Saturday's campaign-ender in Twickenham.
Racing 92 fly-half Geronimo Prisciantelli, Clermont winger Bautista Delguy and Montpellier centre Justo Piccardo are the alterations among the backs.
Up front, there is a new second-row partnership in Pedro Rubiolo and Guido Petti and Santiago Grondona is in at No 8.
The game is being played in London as the UAR seeks to capitalise on a large South African and South American presence in the city.
Felipe Contepomi's side are unable to win the Rugby Championship but the Springboks are top of the table, a point of ahead of New Zealand, who face Australia in Perth earlier on Saturday.
Argentina team to face South Africa:
Backs: Santiago Carreras; Bautista Delguy, Justo Piccardo, Santiago Chocobares, Juan Cruz Mallia; Geronimo Prisciantelli, Simon Benitez Cruz
Forwards: Santiago Grondona, Marcos Kremer, Pablo Matera; Pedro Rubiolo, Marcos Kremer, Pablo Matera; Pedro Rubiolo, Guido Petti, Joel Sclavi, Julian Montoya (capt), Mayco Vivas
Replacements: Igancio Ruiz, Boris Wenger, Francisco Coria Marchetti, Franco Molina, Juan Martin Gonzalez, Joaquin Ovieda, Augustin Moyanoa, Rodrigo Isgro