The men were believed to have been working on the northbound carriageway of the A361 at Gornhay Cross, Tiverton, when they were hit.
One was flown to Plymouth's Derriford Hospital, while a second Devon Air Ambulance flew the other man to the Royal Devon and Exeter Hospital.
The van driver has been arrested on suspicion of dangerous driving.
The condition of the two injured men, who are both in their 40s, is not known.
Devon and Cornwall Police said a third man was hurt in the incident, but he is described as the "walking wounded".
The Barnstaple-bound carriageway is expected to remain closed for several hours and diversions have been put in place.
Two road workers have been seriously hurt in an accident involving a van in mid Devon.