Chasing an improbable target of 549, India were all out for 140 on the final day of the contest with Ravindra Jadeja (54) their top scorer.
Off-spinner Simon Harmer claimed 6-37 for South Africa.
The victory marks just the second time that South Africans have achieved a Test series win in India after 2000.
Meanwhile, the loss by 408 runs marks India’s heaviest defeat (by margin of runs) in Test cricket.
The win has further strengthened South Africa’s position in the ICC World Test Championship 2025-27 standings.
The defending champions occupy the second position, right behind Australia, with 36 points from their four Tests.
On the other hand, India slip below Pakistan in the standings, and are now at the fifth place with their PCT dropping to 48.15.
After a sluggish start on day one, Senuran Muthusamy (109) and Marco Jansen (93) made crucial lower-order contributions to propel the Proteas to 489 in the first innings.
Jansen continued his magic with the ball, snapping figures of 6/48, as the hosts were bundled out for merely 201.
South Africa chose to not enforce the follow-on, instead extending their advantage to past 500, with Tristan Stubbs (94) leading the way in their third innings total of 260/5 before the declaration.
Simon Harmer, South Africa’s Player of the Match in Kolkata, was at his very best in the second innings as well.
Adding to his 3/64 in the first innings, Harmer (6/37) ran through India’s batting line-up on day 5 morning.
While Sai Sudarshan and Ravindra Jadeja mounted resistance, India’s fight broke in the second session as South Africa’s continued strikes meant that they secured a massive 408-run win in Guwahati.
Ravindra Jadeja was the highest run-getter for the hosts with his 54 off 87 deliveries.
Another positive display for the visitors came from Aiden Markram, who stood tall in the field with a couple of stunning catches.
The two teams will now square up in an ODI series starting November 30.
