Mignon du Preez hit a second ODI century with 116 off 99 balls, helping her side to 272-6.
Du Preez added 89 for the sixth wicket with Chloe Tryon (52).
Seamer Masabata Klaas removed Ireland's openers cheaply and the Irish, who had lost Friday's first game by 89 runs, were all out for 204.
South Africa started strongly with openers Laura Wolvaardt and Trisha Chetty adding 65 in 17 overs, but they lost three wickets in four balls when Lucy O'Reilly removed Chetty for 49 and Andrie Steyn for a first-ball duck at the end of the 30th over.
Two balls later, Isobel Joyce bowled Dinesha Devnarain for a duck, and then Sune Luus fell lbw to Ciara Metcalfe for 10 in the 36th over. South Africa slipped from 140-1 to 168-5 but Du Preez led the charge.
She got to her first fifty off 46 balls and needed only 42 balls for the second, stroking 13 fours in the process, to give the Proteas a commanding total.
Clare Shillington and wicketkeeper Mary Waldron contributed forties for Ireland, but Klaas, Luus and Yolani Fourie claimed two wickets each to bowl Ireland out in 48.2 overs.
The sides, who drew 1-1 in a Twenty20 series last week, play further ODI matches on Tuesday and Thursday.
South Africa's women beat Ireland by 68 runs to take an unassailable 2-0 lead in their four-match one-day international series in Dublin.