Ross Adair hit a sensational century as Ireland posted 6-195 batting first in Abu Dhabi on Sunday.
Younger brother Mark then took four wickets, including three in the penultimate over, as Ireland won by 10 runs.
Ireland were well beaten in the previous six meetings between the teams in this format, but this triumph earned them a draw in the two-match series.
Ireland made an impressive start to their innings, smashing 59 without loss during the powerplay.
Skipper Paul Stirling and Ross Adair put on 137 for the first wicket before Patrick Kruger removed the former for 52.
Adair hit a 57-ball century that included nine sixes but was dismissed from the next delivery he faced to leave Ireland 3-174 in the 17th over.
They could only add 20 runs in the remaining 20 deliveries to set World Cup runners-up South Africa 196 to win the series.
South Africa came out firing, with opener Ryan Rickelton hitting four sixes in his 22-ball 36 while Reeza Hendricks and Matthew Breetzke both scored 51.
They looked on course for victory when they started the 19th over needing 23 from 12 balls.
But Mark Adair bowled Wiaan Mulder and dangerman Breetzke in the first three deliveries, then gave up four runs in the next two balls before ending the over by skittling Nqabayomzi Peter.
That left South Africa needing 18 from the final set of six and Graham Hume took a wicket while conceding only seven runs to secure a famous victory.
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