The Proteas served India their biggest home defeat by runs after bowling them out for a dismal 140. India had to chase a mammoth score of 549 on day five in Guwahati.
The World test champs, finished off a 2-0 test sweep against the hosts.
Off-spinner Simon Harmer returned figures of 6-37 as South Africa clinched a Test series in India for only the second time, the first being in 2000 under Hansie Cronje.
Ravindra Jadeja resisted with 54 before Keshav Maharaj had him stumped. The spinner soon claimed the final wicket of Mohammed Siraj, with Marco Jansen pulling off a stunning catch in the deep.
India lost the opening Test in Kolkata inside three days on a pitch with uneven bounce, before South Africa once again beat the hosts at their own game of spin on a batting-friendly track.
The visitors declared their second innings on 260-5 on day four to set India a record chase, but the hosts’ batting once again failed and they never threatened to get close.
India rode their luck early in the day when Jansen had Sai Sudharsan caught behind, but the delivery was declared a no-ball after the bowler overstepped with the batsman on four.
In the next over, another overnight batsman, Kuldeep Yadav, survived a reprieve on four when Aiden Markram dropped him at first slip off Harmer.
The relief was short-lived for India as a relentless Harmer soon bowled Kuldeep for five to claim the first wicket of the day.
The off-spinner then dismissed Dhruv Jurel for two runs three balls later and soon sent back skipper Rishabh Pant for 13 as India slumped to 58-5.
The batsmen fell like ninepins on a pitch where South Africa had posted 489 after electing to bat first.
India were bundled out for 201 to concede a first-innings lead of 288, but South Africa did not enforce the follow-on and decided to bat again.
Left-arm fast bowler Jansen returned figures of 6-48 in India’s first innings after hitting a quickfire 93 with the bat.
South African all-rounder Senuran Muthusamy led the batting charge with his 109, his maiden Test century.
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