De Kock, who reversed a decision to retire from the international game and made himself available again after a two-year absence, scored an unbeaten 123 to ensure a comfortable victory at the Iqbal Stadium and square the three-match series.
South Africa scored 270-2 off 40.1 overs, easily chasing down Pakistan’s 269-9 from their 50 overs.
De Kock featured in an 81-run partnership with teenager Lhuan-dre Pretorius, who scored 46, as they began a strong reply.
But it was the second wicket stand of 153 runs off 137 balls with Tony de Zorzi, who scored 76 off 63 balls, that set up the victory.
De Kock’s 22nd ODI century came up in 96 balls and with captain Matthew Breetzeke he saw his side home with almost 10 overs to spare.
Pakistan won the toss and elected to bat and were reeling at 22-3 in the fifth over, before Saim Ayub (53) and Salman Ali Agha (69) both scored half centuries as they put together a 92-run fourth-wicket partnership.
Mohammad Nawaz chipped in with a career-best 59 to ensure a competitive total for the hosts, who had a narrow two-wicket victory over South Africa in the first ODI on Tuesday.
Left-arm seamer Nandre Burger took 4-46 and leg-spinner Nqaba Peter also bagged career-best figures of 3-55 and were the best bowlers on the night.
The two teams will meet in their deciding fixture, again in Faisalabad, on Saturday.