Three people were injured in the collision that occurred on Sunday on the N2 at Nkodibe, near Mtubatuba, spokesman Kwanele Ncalane said in a statement.
The injured were taken to the Bay Hospital in Richards Bay.
Further details about the collision between the two Hyundai vehicles were not immediately available.
A US embassy official confirmed that two US citizens had been killed. The embassy was not allowed to divulge more information due to US privacy laws, spokeswoman Joy Peters said.
“We are providing appropriate consular assistance to the victims and their families,” she said.