New Zealand Cricket (NZC) said Guptill strained his hamstring during training and was out of this Friday's one-off Twenty20 international against the Proteas in Auckland.
He will also miss two of the five one-day internationals in South Africa's busy touring schedule, which includes three tests.
Rather than call up the vastly experienced Ross Taylor for the T20, the Black Caps instead turned to uncapped 20-year-old Glenn Phillips.
Chief selector Gavin Larsen said the South African-born Aucklander had shown outstanding domestic form and was an exciting prospect.
"He bats with power, has shown he can clear the rope, and gets a deserved opportunity to showcase his skills on the international stage," Larsen said.
Dean Brownlie will replace Guptill in the first two ODIs.
Brownlie was considered unlucky to miss out on the ODI squad in the first place after a strong performance against Australia and Larsen said he was the logical replacement for Guptill.
New Zealand and South Africa have only played 14 T20 internationals, with the Proteas victorious in 10 of them.
They arrive in New Zealand as the world's top-ranked one-day team after winning their last 11 one-dayers, including 5-0 clean sweeps against Australia and Sri Lanka.
They also have added motivation against the New Zealanders after the Black Caps ousted them from the 2015 World Cup in a dramatic semifinal in Auckland.
South Africa's one-day captain AB de Villiers has described that agonising result as "unfinished business", saying the Proteas are keen to exact revenge.
