England flanker Tom Curry will make his first appearance for the British and Irish Lions while Ireland's Iain Henderson will be captain against the Sharks in Johannesburg on Wednesday.
Wales lock Adam Beard and back row Josh Navidi will also make their debuts after being called up as replacements.
Sam Simmonds will make his first international start in three years with Curry and Navidi in the back row.
Tour skipper Conor Murray is among the replacements.
After defeating Japan at Murrayfield, the Lions recorded a first win on South African soil when they thumped the Sigma Lions 56-14 on Saturday.
British and Irish Lions: Williams; Watson, Daly, Aki, Van der Merwe; Biggar, Davies; Vunipola, Cowan-Dickie, Fagerson, Henderson (capt), Beard, Navidi, Curry, Simmonds.
Replacements: Owens, Sutherland, Furlong, Beirne, Conan, Murray, Hogg, Harris.
Curry is yet to play a part in the tour after coming into camp with a pectoral injury while Beard and Navidi joined the team the night before they left for South Africa following injuries to captain Alun Wyn Jones and flanker Justin Tipuric.
Wednesday's fixture is the second of five warm-up games in South Africa before the three-Test series against the Springboks begins on 24 July.
The Lions will face a depleted Sharks side as several of their players - including South Africa captain Siya Kolisi - are preparing for the Springboks' fixture against Georgia on Friday.
Head coach Warren Gatland has said England's Owen Farrell would start at number 10 at some point during the warm-up games but the England captain is not included in the matchday 23.
Instead, Wales' Dan Biggar starts at fly-half with Ireland's Bundee Aki and England's Elliot Daly at 12 and 13 respectively.
After sustaining such significant injuries to Jones and Tipuric against Japan, Gatland said he was pleased "to come through the weekend's game unscathed".
"It's a quick turnaround from Saturday, but we'll be ready to go by Wednesday night," he added.
"We feel like we're slowly building, but, as ever, there's still room for improvement in all facets of our game.
"Wednesday night is another chance for us to have a look at a few more combinations. I'm looking forward to seeing how the back row goes; it's an exciting mixture and one that we hope will offer something a bit different."
Cell C Sharks: Libbok; Kok, Ward, Louw, Abrahams; Bosch, Hendrikse; Mona, Mbatha, Mchunu, Van Heerden, Andrews, Venter, Bholi, Buthelezi (capt).
Replacements: Van Vuuren, Mchunu, Herbst, Van der Mescht, Hugo, Richardson, Williams,Volmink.