Emergency services were called to the incident near Craigielands House at about 12:15.
One man was killed and another was taken to Dumfries and Galloway Royal Infirmary with serious injuries.
Police said the road at the scene would be closed "for some considerable time" to allow for a full crash investigation to take place.
Diversions have been put in place.
A man has been pronounced dead at the scene of a two-car crash on the A701 near Beattock.