Durban - Protesters on Monday used burning tyres and rubble to close off the N3 toll near the Mooi River toll plaza.
Images of a burning truck have been posted on Twitter, but authorities were yet to confirm the authenticity of the photographs.
It was not clear what sparked the protests, which started at dawn, but reports said the road was closed off in both directions early on Monday, the day holiday makers are expected to begin their journeys to go back home. There were also reports of motorists being stoned.
The South African Police Service in KwaZulu-Natal has warned motorists to avoid the N3, which connects Durban and Johannesburg.
"Please be warned that roads around Mooi River is closed and completely inaccessible. Protesters at Mooi River toll gate. The R62, R103 and the N3 north and south bound is closed," said a police tweet.
N3 Toll Concession, the company responsible for the road between Durban and Johannesburg, said: "Total road closure. Please delay your trips. We urge all drivers to be extremely cautious".