Rescue Care and EMRS paramedics arrived on the scene about 30 minutes after midnight and "found carnage", Rescue Care spokesman Garrith Jamieson said.
"It is believed that a vehicle had broken down and a second vehicle had come to assist it when a truck collided into both vehicles and the men. Two men believed to be in their 20s and 50s respectively had suffered major injuries and there was nothing paramedics could do for them; they were declared deceased on the scene."
Another man, also in his 20s, was found trapped under his vehicle and the Durban fire department had to use special equipment to free the seriously injured man while advanced life support paramedics worked to stabilise him.
Once freed, he was transported to a nearby hospital for the further care that he required.
The South African Police Service (SAPS) search and rescue unit was called to the scene to assist, as on impact one of the men had been flung down an embankment.
The M7 was closed while the SAPS conducted their investigation, Jamieson said.