Chasing 266 to record its first ever series-win on South African soil, India were tottering at 137 for six in 31.3 overs, 50 runs behind the par score, when rain stopped play.
When play resumed after more than an hour's break, India were set a revised target of 260 from 46 overs but only eight balls could be bowled and skies opened up again, leading to another forced break.
Play never resumed again and the umpires called off the match with South Africa emerging winners. Both the sides will now travel to Centurion for the fifth and final match.
Virat Kohli waged a losing battle all alone as the other Indian batsmen surrendered abjectly.
The Delhi dasher gradually got into the groove and then took the South African attack by the scruff off its neck but ran short of partners as wickets kept tumbling from the other end.
Earlier, it was J P Duminy's defiant unbeaten knock of 71 and his crucial stands with the lower order batsmen that helped South Africa post a challenging 265 for seven after opting to bat at St George Park.
India had taken good control over the match by reducing South Africa to 118 for five at one stage but Duminy's never-say-die spirit and the resultant fifty negated all the good work done by the visiting bowlers.
Kohli did well for India as he single handedly took the fight and played an entertaining knock which came off just 92 balls with seven fours and two sixes.
It was paceman Lonwabo Tostsobe (2/25), who rocked the Indian innings early on with his two wickets and the visitors found hard to recover.
India's chase began on a shaky note with Rohit Sharma (1) failing yet again as an opener but that did not stop Parthiv Patel, who was playing his first match of the series, and Kohli playing some attacking shots.
Twice Patel (11) sent ferocious Dale Steyn to the boundary ropes and Kohli took 10 runs from Tsotobe's one over with two shots to the fence.
However, both the batsmen soon slowed down due to the slow nature of the track as playing fluent shots was not easy.
Tsotsobe jolted the Indian chase as he first had Rohit Sharma (1) caught at backward point and then trapped Patel, who replaced injured Sachin Tendulkar in the side.
India had still not crossed the 50-run mark and 15th over was on when Yuvraj Singh hammered spinner Johan Botha for a six to give momentum to the innings but a top edge off a sweep shot in the same over ended his stay the crease.
Host skipper Graeme Smith ran from the slip cordon and dived full stretch to convert that half chance.
Runs were hard to come by but Kohli and Suresh Raina kept moving the scorecard with singles and twos and in the process the Delhi batsman completed his fifty off 67 balls.
Kohli swung his arms to good effects after getting his fifty as he hit a four off Duminy and a classy and effortless long-off six off Robin Petersen.
The hapless Petersen was hit for another six by Kohli in his next over but the host spinner made up by scalping India skipper Mahendra Singh Dhoni (2).
India's last match hero Yusuf Pathan (2) survived a big appeal in the first ball he faced from Petresen but perished soon as he nicked one off Morne Morkel to leave India tottering at 128 for six.
Earlier, Duminy came up with the fighting knock when the chips were down for the hosts as except for Hashim Amla (64), none of the top-order Proteas batsmen could convert starts.
Apart from the good job done by India's part time bowlers, the three inexplicable run outs prevented South Africa from getting a better scorecard.
India's spinners did a decent job in the middle overs by checking the run flow and Yuvraj Singh (3/34) was quite effective as he took three wickets.
Duminy came on to bat in the mid of the South African innings and batted till the last over as he shared two crucial partnerships with Johan Botha (44) and Robin Petersen (31).
Duminy's determination reflected in his 72-ball knock as he hit just two boundaries and a six, which came in the 50th over, and ran hard to anchor the hosts innings.
South Africa had lost five wickets at the score of 118 but Duminy and Botha dug in and steadied the rocking ship with their 70-run partnership for the sixth wicket.
Earlier, after a rather sedate start, South African openers Smith and Amla gradually accelerated the pace of scoring by hitting a few boundaries.
While Amla showed his aggressive intent by clobbering Munaf Patel to the boundary, Smith picked up Zaheer Khan for special treatment by spanking for two boundaries.
Amla suddenly broke free and slammed a flurry of delightful boundaries to take South Africa's score beyond the 50 mark in quick time.
Paceman Ashish Nehra provided the breakthrough when he got the prized scalp of Smith (18).
The South African captain went down the track and flat batted it towards mid-off where Harbhajan Singh took a brilliant catch.
Amla continued to play aggressively at the other end and notched up his half century with a boundary off the bowling of part-timer Yuvraj Singh.
The complexion of the game changed dramatically after that as the hosts slumped to 118 for five as Amla (65), Morne van Wyk (15), A B de Villiers (3) and Faf du Plassis (1) perished in quick succession.
Scorecard of the fourth cricket One-day international between India and South Africa at St George's Park here today.
South Africa innings:
H Amla run out 64
G Smith c H Singh b A Nehra 18
M van Wyk c Kohli b Y Singh 15
AB de Villiers c Dhoni b Y Singh 3
JP Duminy not out 71
F du Plessis run out 1
J Botha st Dhoni b Y Singh 44
R Peterson run out 31
D Steyn not out 4
Extras (B-1, LB-1, WD-10, NB-2) 14
Total (For 7 wickets in 50 overs) 265
Fall of wickets: 1-57, 2-106, 3-111, 4-115, 5-118, 6-188, 7-242.
Bowling: Z Khan 9-1-55-0, M Patel 8-1-49-0, A Nehra 6-0-27-1, Harbhajan Singh 10-0-61-0, Yuvraj Singh 8-0-34-3, R Sharma 2-0-6-0m, S Raina 3-0-13-0, Y Pathan 4-0-18-0.
India:
Rohit Sharma c Duminy b Tsotsobe 1
Parthiv Patel lbw b Tsotsobe 11
Virat Kohli not out 87
Yuvraj Singh c Smith b Botha 12
Suresh Raina st Villiers b Peterson 20
MS Dhoni c du Plessis b Peterson 2
Yusuf Pathan c de Villiers b Morkel 2
Harbhajan Singh not out 3
Extras (LB-2, WD-2) 4
Total (For 6 wickets in 32.5 overs) 142
Fall of wickets: 1-1, 2-32, 3-49, 4-112, 5-123, 6-128.
Bowling: D Steyn 4-0-15-0, L Tsotsobe 6-1-25-2, M Morkel 6-1-13-1, J Botha 6.5-0-27-1, R Peterson 8-0-46-2, F du Plessis 1-0-5-0, JP Duminy 1-0-9-0.