Janneman Malan and Quinton de Kock produced a stunning 225-run opening partnership to set up victory over Ireland on Friday, although the bowlers then laboured as the Proteas ultimately came away with just a 70-run win.
Ireland were eyeing their first ODI campaign success against a top-eight nation after a 43-run win on Tuesday put them 1-0 up following a washed-out opener.
But Janneman Malan’s career-best 177* and a hundred from Quinton de Kock took the Proteas to an imposing total of 346-4 on Friday.
That left Ireland needing to surpass their previous highest successful chase, of 329 against England last year, for victory.
It was a task that proved beyond them, despite Simi Singh’s 100* in a total of 276.
South Africa’s Andile Phelukwayo and Tabraiz Shamsi took three wickets apiece.
The two teams now shift their focus to the three-match T20 series, with the first T20 scheduled on Tuesday in Dublin.
Paul Stirling, Andy Balbirnie (captain), Andy McBrine, Harry Tector, George Dockrell, Mark Adair, Curtis Campher, Lorcan Tucker (wkt), Simi Singh, Josh Little, Craig Young
Quinton de Kock, Janneman Malan, Temba Bavuma (captain), Rassie van der Dussen, Kyle Verreynne (wkt), Heinrich Klaasen, Andile Phehlukwayo, Keshav Maharaj, Anrich Nortje, Lizaad Williams, Tabraiz Shamsi.