By virtue of this win, India have taken an unassailable 2-0 lead in the series, which is part of the ICC Women's Championship.
Sent into bat, left-handed Mandhana started from where she left in the first game and smashed 135 off just 129 balls to form the base for India's 302 for three.
She hit 14 boundaries and a six en route to her century. Incidentally, this is Mandhana's second ODI century against South Africa.
Besides Mandhana, Harmanpreet Kaur (55 not out) and Veda Krishnamurthy (51 not out) contributed to India's total.
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Opener Punam Raut (20) and skipper Mithali Raj (20) also got starts but failed to prolong their stay at the crease.
All the South Africa bowlers looked helpless in front of the Indian batswomen as they could just manage to take three wickets with Sune Luus registering best figures of one for 31.
Just like the first ODI, Indian bowlers too were clinical in their approach, bowling out South Africa for just 124 runs in 30.5 overs to register yet another massive win.
India's veteran pacer Jhulan Goswami also added another feather to her illustrious cap today by becoming the first female cricketer to take 200 ODI wickets.
The 35-year-old Goswami, playing her 166th ODI, achieved the feat when she dismissed opener Laura Wolvaardt for her 200th scalp.
South Africa's struggle against the Indian attack can be gauged from the fact that only two of their batswomen could manage double digit scores.
The only other South African batswoman to have reached double digit score was Marizanne Kapp, who remained unbeaten on 17.
Brief Scores:
India women: 302 for 3 in 50 overs (Smriti Mandhana 135; Sune Luus 1/31).
South Africa women: 124 all out in 30.5 overs (Lizelle Lee 73; Poonam Yadav 4/24).