In the other big selection call, Craig Casey has been chosen to take the place of the injured Jamison Gibson-Park at scrum-half.
The 25-year-old Munster player has 14 caps for the side, but only four of those have come in starts.
The experienced Conor Murray has been named among the replacements for the Test at Loftus Versfeld Stadium.
Elsewhere, Robbie Henshaw is selected ahead of Garry Ringrose to partner Bundee Aki in midfield, while Tadhg Beirne and Joe McCarthy will continue their partnership in the second row.
Captain Peter O’Mahony, Josh van der Flier and Caelan Doris form a familiar-looking back row, with James Lowe and Calvin Nash on the wings.
On the bench, Farrell has opted to go with a split of five forwards and three backs.
In addition to Keenan, wing Mack Hansen – who scored tries against South Africa in 2022 and 2023 – is absent from the tour as he recovers from a shoulder injury.
South Africa’s team, which was named on Tuesday, features 12 World Cup winners.
Ireland: J Osborne; C Nash, R Henshaw, B Aki, J Lowe; J Crowley, C Casey; A Porter, D Sheehan, T Furlong; T Beirne, J McCarthy; P O’Mahony (capt), J van der Flier, C Doris.
Replacements: R Kelleher, C Healy, F Bealham, J Ryan, R Baird, C Murray, C Frawley, G Ringrose.