The men took the safe from the Jet garage at Bowburn at about 12:15 GMT, along with a silver Vauxhall Astra belonging to a woman working in the shop.
Durham Police said the car and safe were found abandoned nearby.
The robbers were wearing balaclavas and police are appealing for witnesses to come forward.
Det Insp Dunny McCubbin said: "This was obviously a terrifying incident for the woman and we would urge anyone who has any information either about the robbery or the abandoned car to get in contact."
Four masked men have carried out a "terrifying" robbery at a petrol station close to Durham city.