Spurred on by De Kock, South Africa needed just 27.2 overs to reach 171-3 and easily chase down Zimbabwe's 165 all out at Queens Sports Club.
De Kock plundered seven fours and two sixes and appeared to be racing to a sixth century of his young career when he smashed a catch straight to Sean Williams near the mid-wicket boundary with South Africa only 22 short of the target.
JP Duminy finished the game with a six to end 28 not out as the Proteas cruised to a fourth success in Zimbabwe after also winning the one-off Test. Stand-in captain Faf du Plessis made 40.
South Africa rested a string of top players through the series in Bulawayo and was still a class above the Zimbabweans.
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Front-line fast bowlers Dale Steyn, Vernon Philander and Morne Morkel sat out the entire ODI series ahead of a triangular tournament also involving Australia. Regular ODI skipper AB de Villiers and Hashim Amla were rested for the final game.
Without them, South Africa still retained its record of winning every ODI series it has contested against Zimbabwe. The second-string pace attack of Marchant de Lange, Kyle Abbott and Wayne Parnell was easily good enough.