Pakistan were bowled out for 209 in 49.4 overs with Ahmed Shehzad top-scoring with 58 while Ryan McLaren (4-34) and Mornke Morkel (3-38) shared the bowling honours.
South Africa could not cope against Pakistan's slow bowlers as they were dismissed for 143 in 40.4 overs. McLaren top-scored with 29 not out.
South Africa won the first one-dayer in Sharjah by one run.
The remaining matches will be played in Abu Dhabi (November 6 and 8) and in Sharjah (November 11).
Brief scores: Pakistan 209 in 49.4 overs (Ahmed Shehzad 58; R. McLaren 4-34, M. Morkel 3-38); South Africa 143 in 40.4 overs (R. McLaren 29 not out, Shahid Afridi 3-26, Mohammad Irfan 3-53).