The Springboks, who led the series 2-1 after the opening three Tests in South Africa, produced a devastating second-half display at Baltimore's M&T Stadium to seal victory.
Tries from Damian de Allende, Morne van den Berg, Malcolm Marx, Pieter-Steph du Toit, Kurt Lee Arendse and Cameron Hanekom clinched a deserved win for the Springboks in front of a capacity 71,000 crowd.
New Zealand's tries came from recalled captain Codie Taylor, Will Jordan, Ethan Blackadder and Beauden Barrett, but the All Blacks were always chasing the South Africans in a fast-paced game.
There was controversy in the first half when play was held up for more than eight minutes after a failure in communication equipment between the match officials.
But that interruption had no impact on the outcome as South Africa's total dominance at the breakdown, set piece and aerial battle proved decisive.
Springbok captain Siya Kolisi paid tribute to South Africa coach Rassie Erasmus following the victory.
"He knows how to get us up, and when he speaks to us he reminds us where we come from, the country that we come from," Kolisi said.
"The players who are in the group who are not playing. We do it for them. The guys that are injured, the guys that couldn't make the tour, and also for the people of South Africa."
New Zealand skipper Taylor, meanwhile, had few complaints with the defeat.
"We talk a lot about moments throughout the week when we review our Test matches and South Africa just stacked a few more moments against us over the last couple of games," the veteran hooker said.
"Full credit to them - they're a great side and they've proven why they're world champions."
Taylor, though, said New Zealand would take positives from the series defeat as they build towards the 2027 Rugby World Cup.
"It's a good stepping stone," he said. "We're at an interesting place at the moment as a rugby nation. We've fallen short in this series but I can assure you and everyone back home that we're working hard."