Aiden Markram is leading South Africa in the opening game of the three-match series after regular skipper Temba Bavuma was ruled out because of illness.
South Africa's majority of frontline white-ball players are either being rested or playing in a T20 domestic league in the West Indies.
Middle-order batter Jason Smith was handed his ODI debut in the absence of Heinrich Klaasen and David Miller. Reeza Hendricks gets an opportunity at the top of the batting order after having a below-par T20 World Cup in June.
South Africa also picked aggressive T20 batter Tristan Stubbs at No.4, who is playing only his second ODI and had an impressive year in the shortest format of the game.
Afghanistan are without injured batter Ibrahim Zadran and ace spinner Mujeeb Ur Rahman in their first-ever bilateral ODI series against South Africa.
Afghanistan skipper Hashmatullah Shahidi hoped the dry wicket at the United Arab Emirates' Sharjah Cricket Stadium, hosting its 250th ODI, will suit the spinners.
"We would have batted first," Shahidi said at the toss. "We have played a lot of cricket on this wicket … hopefully it will support spinners."
South Africa: Tony de Zorzi, Reeza Hendricks, Aiden Markram (capt), Tristan Stubbs, Kyle Verreynne, Jason Smith, Wiaan Mulder, Andile Phehlukwayo, Bjorn Fortuin, Lungi Ngidi, Nandre Burger.
Afghanistan: Rahmanullah Gurbaz, Riaz Hassan, Rahmat Shah, Hashmatullah Shahidi (capt), Mohammad Nabi, Nangeyalia Kharote, Azmatullah Omarzai, Gulbadin Naib, Rashid Khan, AM Ghazanfar, Fazalhaq Farooqi.
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