Images from the scene have shown scores of people standing on the side of the road amid thick mist in the area.
The cause of the accident remains unclear.
Paramedics were yet to confirm any injuries or fatalities.
According to the uMngeni municipality, however, several fatalities have been reported.
“Motorists are urged to avoid the N3 between Pietermaritzburg and Cedara [especially JHB bound].The highway is closed heading from Durban to Johannesburg in the vicinity of Hilton,” said Sandile Mnikathi, uMngeni municipality deputy mayor.
“The area is very misty, and the long weekend traffic has made things worse. uMngeni Traffic has five vehicles attending to the scene in support of RTI and Msunduzi Traffic,” read a statement from Mnikathi.