Guptill smashed three sixes and six fours as he bludgeoned 60 from 35 balls to lead the tourists to 177 for seven.
The Proteas were in trouble early in their chase and battled to keep up with the rate, managing 145 for eight in reply.
New Zealand won the toss and Guptill and captain Kane Williamson (25) put on 52 for the first wicket.
Jimmy Neesham (28 from 19 balls) also played a fine cameo as the visitors finished their innings strongly after the platform laid by Guptill.
Young fast bowler Kagiso Rabada was the pick of the home bowlers with three for 30 in his four overs, including two wickets in as many balls for the second match running.
South Africa started slowly and when AB de Villiers (15) tried to up the rate he was caught by Neesham off spinner Nathan McCullum before they slipped to 47 for three in the seventh over.
Farhaan Behardien (36), David Miller (29) and Rilee Rossouw (26) tried to rebuild, but could not get South Africa close to their target.
The teams start a three-match one-day international series at the same venue on Wednesday.
