Flanker Ben-Jason Dixon and utility back Sacha Feinberg-Mngomezulu are also likely to make their debuts off the bench as coach Rassie Erasmus opts for a rare, for him, 5-3 split between forwards and backs among the replacements.
The fixture in London falls outside of the international window, leaving the Springboks without several of their first choice players in England and France, as well as those from the Bulls, who host Glasgow Warriors in the United Rugby Championship final on the same day.
"Edwill, Jordan, Ben-Jason, and Sacha have really impressed us at training, and we believe they have what it takes to make their presence felt against a quality team such as Wales," Erasmus said.
"They will be surrounded by several experienced campaigners – some of whom are Rugby World Cup winners – so they will have enough guidance on the field to fulfil their roles even when the pressure is on."
Hendrikse is the younger brother of scrumhalf Jaden, who was a World Cup winner with the Springboks in France last year, but is currently out injured.
Jordan, 22, has been preferred to Manie Libbok in a surprise selection from Erasmus, who is never shy to experiment and go against expectations.
Aphelele Fassi will be at fullback with the experienced Makazole Mapimpi on the opposite wing to the electric Van der Merwe, who is in a similar mould to Cheslin Kolbe and Kurt-Lee Arendse with quick feet and pace to burn.
Andre Esterhuizen and Jesse Kriel are the centre pairing, with double World Cup winner Faf de Klerk alongside Hendrikse at halfback.
Malcolm Marx makes a return at hooker after his World Cup in France was cut short by a serious knee injury, and will have props Ox Nche and Vincent Koch, who wins a 50th cap, alongside him in a formidable front row.
Eben Etzebeth and Franco Mostert are the lock pairing, with Kwagga Smith and Du Toit on the flank, and Evan Roos at number eight.
The three backs on the bench are halfback Grant Williams, Feinberg-Mngomezulu, 22, who can cover five eighth, centre and fullback, and centre Damian de Allende.
The Springboks are also without several players with injuries, including Steven Kitshoff, Damian Willemse, Lukanyo Am and Kolbe.
South Africa team to face Wales:
15-Aphelele Fassi, 14-Edwill van der Merwe, 13-Jesse Kriel, 12-Andre Esterhuizen, 11-Makazole Mapimpi, 10-Jordan Hendrikse, 9-Faf de Klerk, 8-Evan Roos, 7-Pieter-Steph du Toit (captain), 6-Kwagga Smith, 5-Franco Mostert, 4-Eben Etzebeth, 3-Vincent Koch, 2-Malcolm Marx, 1-Ox Nche
Replacements: 16-Bongi Mbonambi, 17-Ntuthuko Mchunu, 18-Frans Malherbe, 19-Salmaan Moerat, 20-Ben-Jason Dixon, 21-Grant Williams, 22-Sacha Feinberg-Mngomezulu, 23-Damian de Allende.
