Prendergast has been fighting it out with Jack Crowley for the number 10 jersey for the past year. While his Munster rival started against New Zealand and Japan after some fine club form, Prendergast played well in last weekend's 46-19 drubbing of Australia.
Centre Ringrose and back-row Van der Flier - two of the current squad's most capped players - have recovered from hamstring strains, having missed the last two tests against Japan and Australia.
Andrew Porter, given a rare breather last week, returns to the front row, while Bundee Aki partners Ringrose in the centre.
Mack Hansen remains in the unfamiliar spot of fullback, having scored a hat-trick of tries in the first half against his native Australia.
"South Africa are the world champions and we know the challenge that awaits us this weekend," Farrell said in a statement.
"Whenever you face a top side you know that you have to be on top of your game and that you will be tested and we'll look to build on the momentum from last weekend and approach the game positively."
The top-ranked Springboks have won all three games so far on tour after defeating Japan, Italy and recording a particularly impressive victory away to Six Nations champions France.
Ireland team:
15-Mack Hansen, 14-Tommy O'Brien, 13-Bundee Aki, 12-Garry Ringrose, 11-James Lowe, 10-Sam Prendergast, 9-Jamison Gibson-Park, 1-Andrew Porter, 2-Dan Sheehan, 3-Tadhg Furlong, 4-James Ryan, 5-Tadhg Beirne, 6-Ryan Baird, 7-Josh van der Flier, 8-Caelan Doris (captain)
Replacements: 16-Ronan Kelleher, 17-Paddy McCarthy, 18-Finlay Bealham, 19-Cian Prendergast, 20-Jack Conan, 21-Craig Casey, 22-Jack Crowley, 23-Tom Farrell.
