The thumping 177-run victory - Afghanistan's biggest in ODIs by runs - came just two days after Afghanistan beat the Proteas for the first time.
Also, Rahmanullah Gurbaz's 105 made him the first Afghan man to hit seven ODI hundreds.
Their strong total of 4-311 in sweltering heat was followed by South Africa being all out for 134 in the 35th over.
Leg-spinner Rashid Khan, who injured his hamstring while batting, celebrated his 26th birthday with 5-19 and left-arm spinner Nangeyalia Kharote claimed 4-26.
Afghanistan will eye a series sweep in the final ODI on Sunday.
"I had a hamstring (injury), but I tried my best to stay on the ground and do my best for the team," Rashid said.
"It was a great opportunity for us to win the series against a big team … I really enjoy youngsters like Kharote and (Allah) Ghazanfar, we share ideas with them. It was great to see youngsters coming up and showcasing talent on the big stage against South Africa."
Gurbaz and then Azmatullah Omarzai laid the foundation for Afghanistan's first 300-plus score against South Africa in an ODI.
Gurbaz and Rahmat Shah combined for a 101-run partnership for the second wicket.
The 90s brought some nervy moments for Gurbaz. On 99, he played a maiden over from Bjorn Fortuin then swept Aiden Markram to square leg. He celebrated his century by making a heart shape with his hands and blew a kiss to his teammates in the dressing room.
Nandre Burger made the breakthrough when he bowled Gurbaz for 105 off 110 balls, including 10 boundaries and three sixes. But Gurbaz's exit brought on Omarzai.
He hit an unbeaten 86 off 50 balls, while Shah added 50 off 66. Omarzai smashed six sixes and five fours as Afghanistan scored 93 runs in the last 10 overs.
"Congrats to our nation," captain Hashmatullah Shahidi said. "We're happy here and all people back home will be happy.
"In the batting, the way Gurbaz started and then Rahmat and Omarzai carried on, all of them were very good. When it comes to bowling, I know the spinners will deliver it for me."
South Africa's bowlers struggled in the humidity and only spinners Fortuin and Markram kept the batters quiet for some time by conceding 59 runs off their 14 overs.
South Africa's chase started promisingly. The return from illness of captain Temba Bavuma gave the Proteas some hope. He scored 38 and put on 73 runs for the opening wicket with Tony de Zorzi, who made 31.
But after Bavuma top-edged a pull shot against Omarzai's short-pitched delivery, an inexperienced South Africa side collapsed.
South Africa lost seven wickets for 39 runs before Rashid completed a five-wicket haul by clean bowling Markram on 21. Kharote completed the rout.
It was a near replica of the first ODI when South African were reduced to 7-36 inside the first 10 overs.
"Not a good enough performance," Bavuma said. "We were not able to take 10 wickets and that's a conversation we need to have.
"Omarzai put us under pressure in the middle and that's the reason they got to that score after Gurbaz gave the foundation. They were a lot better than us clinically."
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