Guptill was 103 not out as New Zealand cruised to 207-2 after bowling South Africa out for 204.Doug Bracewell took ODI career-best figures of 3-31 for New Zealand to help restrict the South Africans at Senwes Park.
Guptill then clobbered nine fours and three sixes and shared an opening stand of 126 with Tom Latham, who made 64.
The Black Caps' big win sends the series to a deciding game in Durban next week and continues the seesaw limited-overs tour. The teams drew the Twenty20 series 1-1, with South Africa taking the first game and New Zealand coming back to win the second.
New Zealand beats Bangladesh by 8 wickets in 3rd ODI