A 29-seat coach crashed into a water tank truck at section 44km+800 of the HCM City-Trung Luong expressway in Tien Giang province at 09.30am.
The coach, with several foreigners on board, was travelling from Tien Giang to Ho Chi Minh City when the accident happened, witnesses said.
Three passengers died at the scene and another passed away on the way to hospital. Among the deaths were a male foreigner and a child aged between 10 and 12.
A tow truck was dispatched to separate the damaged coach from the water tank truck.
It took rescue workers half an hour to extricate victims who were trapped in the wreckage.
Investigations into the cause of the accident are underway.