Reeza Hendricks, the Proteas’ in-form opener, led the team with 42 points, while Heinrich Klaasen added 39 as they set a goal of 182-6.
As Ireland’s response dragged on at 2-2, Andy Balbirnie and Lorcan Tucker both failed to score, but Paul Stirling’s 28 and Harry Tector’s 34 helped them come back.
Ireland reached 138 all out because of Barry McCarthy’s tenacious defense, which he led with 32.
Ireland was bowled out with seven balls to spare despite the tailender’s valiant attempt.
The left-arm quick’s first five-wicket T20 international haul of 5-30 was significant in causing Ireland to suffer their eighth straight loss at this level.
Early on, Parnell hindered Ireland’s pursuit by grabbing two wickets in a row.
After scoring 78 in the first T20, which Ireland lost by 21 runs, Tucker went first ball when he miscued to mid-on. Balbirnie was out for an eight-ball duck when he chipped to cover.
With the help of the seasoned Paul Stirling, the in-form Tector recovered from the hat-trick and began to heal the damage.
When Stirling missed a draw-off fast bowler Lungi Ngidi, he was dealt a nasty knock to the groyne. Stirling had smashed two fours and two sixes in a total of 28.
His downfall came on the next ball when Stirling sliced a slower ball from Ngidi, and Aiden Markram made the catch while sprinting from point to short third man.
Gareth Delany was out for a duck by left-arm wrist spinner Tabraiz Shamsi with Ireland leading 40-4.
After that, in a span of three balls, Parnell claimed two more wickets: Curtis Campher was caught behind a reverse sweep, and Tector was out for 34 after a botched pull.
Then, in his 45th game at this level, Parnell grabbed the fifth wicket when Quinton de Kock, the wicketkeeper, spectacularly caught Andy McBrine.
Ireland’s final score was 96-9, and although McCarthy’s dramatic run-out thrilled the spectators, it did little to save loss.
Earlier, the Proteas could reach their goal thanks to South Africa skipper David Miller’s unbeaten 32 and a quick 71-run partnership with Klaasen in 33 balls.
After tight Ireland bowling initially left South Africa struggling for runs, with opener De Kock being out cheaply, Miller, who missed Wednesday’s game with back spasms, struck three sixes.
After Hendricks was just sent out for 42, missing out on a sixth straight T20 international fifty, Klaasen’s 39 came in only 16 balls.
But after leg-spinner Delany’s 2-24, Ireland again took control of the situation on the field.
Before deciding on a team for the T20 World Cup, which would go to India for a three-match series in September before the championship event in Australia, this was South Africa’s penultimate game at this level.
Later this month, Ireland will host Afghanistan for a five-match series.