Having been put in to bat, Ireland were all out for 104 in 18.3 overs, with Tumi Sekhukhune (3-20), Nonkululeko Mlaba (2-15) and Nadine de Klerk (2-23) doing most of the damage.
Lara Goodall (48 off 32 balls) and Anneke Bosch (44* off 37) then fired with the bat as South Africa reached their target in the 14th over to complete a come-from-behind 2-1 series win.
Ireland won the first match by 10 runs before South Africa bounced back with an eight-wicket win in the second.
The teams will now contest a three-match ODI series in Dublin, which starts on Saturday.
