The Proteas completed a successful chase of the 180 run target set by Pakistan in the 39th over, with AB de Villiers not out on 48.
Saeed Ajmal bagged the Man-of-the-Series award whereas Vernon Philander was declared Man-of-the-Match.
South Africa made a steady start to their innings, but a regular fall of wickets from the sixth over onwards saw Pakistan get back in to the game.
Pakistan had opted to rest Mohammad Hafeez, Shahid Afridi and Junaid Khan for the game, replacing them with Umar Amin, Asad Shafiq and Sohail Tanvir.
Veteran spinner Saeed Ajmal tried his best to restrict the hosts and managed to take two important wickets in his full quota of overs at the expense of 34 runs.
Bilawal Bhatti, Sohail Tanvir and Abdur Rehman took a wicket each as well.
In the end, though, 179 runs turned out to be too few to defend as formidable run-making from Hashim Amla (41) and AB de Villiers (48), coupled with smaller contributions from other batters, was enough to take the hosts to victory.
Earlier, the visitors put on another miserable batting show, crumbling away for just 179 runs despite 'lone warrior' captain Misbahul Haq battling on 79 unbeaten.
The South African pace attack, weakened by the absence of Dale Steyn, took to the field with a pre-planned agenda of bouncing the batsmen out.
The Pakistani batting lineup, which has been suspect against any type of bowling in recent times, particularly ducked in the face of menacing bounce, eventually getting dismissed by the 47th over.
Apart from Misbahul Haq, only Umar Amin, Sohaib Maqsood and Abdur Rehman could manage to get into double figures.
Misbah though proved to be the only bit steel in the line up, staying unbeaten till the end of the innings with an impressive individual score that was just shy of eclipsing the overall team total.
Misbah had amassed 79 runs from 107 balls with four fours and two sixes, when Pakistan's last wicket fell with Saeed Ajmal edging off Wayne Parnell in the 47th over.
From the Proteas side, each bowler managed to grab at least one wicket. Philander took three, Tsotsobe, McLaren and Tahir took two each, while Parnell took one.
Pakistan had already won the three match series, becoming the first Asian side to secure ODI series in South Africa following a tight one-run win in Port Elizabeth in the second match on November 27. It was also their maiden ODI series triumph against the Proteas.
Teams
Pakistan
Umar Amin, Ahmed Shehzad, Asad Shafiq, Sohaib Maqsood, Misbahul Haq (c), Umar Akmal†, Bilawal Bhatti, Anwar Ali, Abdur Rehman, Sohail Tanvir, Saeed Ajmal
South Africa
Q de Kock†, HM Amla, H Davids, JP Duminy, AB de Villiers, DA Miller, R McLaren, WD Parnell, VD Philander, LL Tsotsobe, Imran Tahir
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