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.

The route between Edinburgh and Tweedbank had been hit by delays and cancellations.
ScotRail apologised for the problems and said buses had been organised to supplement the trains that could run.
More minor disruption on the route between the Borders and Edinburgh was cleared by about 16:00.

A review of homes in Wales said they were seen as places of "irreversible decline" where residents were unable to do things that matter to them.
The report was published by the Older People's Commissioner for Wales.
The Welsh government said it was already taking action on issues raised in the report, A Place to Call Home?
Care Forum Wales, which represents 500 care providers, said the findings support what it has long been saying.
Experts in health and social care undertook unannounced visits to 100 care homes across Wales.
And more than 2,000 questionnaires were completed by care home residents and their families.
The report's key conclusion was: "Too many older people living in care homes quickly become institutionalised. Their personal identity and individuality rapidly diminishes and they have a lack of choice and control over their lives."
It looked at residents' social participation, their home environment, diet, staffing and training as well as commissioning, regulation and inspection of services.
Commissioner Sarah Rochira called "for action to deliver the change required within our care homes and ensure that quality of life sits at the heart of the delivery of residential and nursing care across Wales".
She said: "While my review found excellent examples of truly person-centred care, enabling and empowering care that delivers the very best outcomes for older people, there are significant variations across Wales that result in too many older people living in care homes having an unacceptable quality of life."
The review was undertaken using the commissioner's statutory powers which means care providers and public bodies have to act on the findings.
Care and Social Services Inspectorate Wales (CSSIW) chief inspector Imelda Richardson said it had moved away from a tick box culture to focusing on quality of life of people during its inspections of older people's care homes in Wales.
She said while the majority of care homes provide good or excellent care, there is "still an unacceptable level of care in some homes".
Care Forum Wales chair Mario Kreft said the report did not "fully recognise what is being achieved despite the system".
He supported a call for services being commissioned for quality rather than reinforcing a "culture of compliance to the bare minimum".
He added: "The commissioning process should be about quality and securing value for money and not about paying the lowest possible price."
A Welsh government spokesperson said: "The Welsh government, for its part, is already taking action on many of the areas highlighted in this report through a draft Bill to strengthen the regulation and inspection of social services.
"We expect the care sector to consider this report carefully - as the Welsh government will - and reply to the Older People's Commissioner's specific points."
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.
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Services on the Borders Railway are "running as normal" after severe disruption due to signalling problems.
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Many older people living in care homes have an "unacceptable quality of life" and quickly become institutionalised, says a watchdog.