South Africa, who won the toss and batted, posted a challenging total of 259-8 with Jean-Paul Duminy scoring 64 and Faf du Plessis a return-to-form 55 before bowling out Pakistan for 191 in 44.3 overs.
Leg-spinner Imran Tahir took 4-53. For Pakistan Wahab Riaz top-scored with 33 while Ahmed Shehzad made 32.
South Africa won the first match by one run in Sharjah while Pakistan won the second in Dubai by 6 runs.
The remaining matches will be played in Abu Dhabi on Friday and Sharjah on Monday.
Score summary: South Africa 259-8 in 50 overs (JP Duminy 64, Faf du Plessis 55; Mohammad Irfan 3-45); Pakistan 191 in 44.3 overs (Wahab Riaz 33, Ahmed Shehzad 32: Imran Tahir 4-53).