Police closed the Gretna to Stranraer route near the junction with the B794 Dalbeattie to Corsock Road after the accident, which happened around 11.55 am.
The vehicles involved were a red-coloured Nissan van being driven by a 48-year-old man from Springholm; a red-coloured VW Tiguan driven by a 70-year-old man from Dalbeattie and a white-coloured Daf lorry driven by a 57-year-old Stranraer man.
The drivers of the Nissan van and the VW Tiguan were conveyed to Dumfries and Galloway Royal Infirmary where they were treated for serious injuries.
PC Callum Kingstree said: “We are keen to hear from anyone who may have witnessed this crash and would ask that they call us at Castle Douglas on the 101 number. The road was blocked for over two hours to allow for the injured to be removed to hospital and the damaged vehicles to be taken away.”