The train was traveling from Mashhad to Yazd when it derailed near the city of Tabas at 5:30 am local time.
Authorities said it has collided with an excavator on the railroad.
The accident has killed 13 passengers and injured at least 50 others, 15 of whom are in critical conditions, medics said.
The governor of Tabas said four train cars have derailed in the accident.
Helicopters and ambulances from three provinces have been dispatched to the disaster scene.
In recent years, Iran has added hundreds of new train cars manufactured or renovated domestically to the railroad network in order to modernize its aging fleet.
In September 2019, a train derailment in Sistan and Balouchestan Province killed three people and injured 35 others.