In order to solve the difficulty of reliable cooperative operation of five-prevention system in regional substations, a blockchain-based intelligent five-prevention control method for regional substations is proposed. Firstly, the communication channel between substations is established through virtual private network to realize the secure communication between substations. Then, the blockchain technology is used to establish the five-prevention trusted authentication mechanism of the equipment among the regional substations to achieve the trusted cooperative five-prevention operation of the regional substations. Finally, the method is applied in the simulation environment of a regional substation in a province to implement the intelligent five-prevention control of regional substation. The simulation results show that the correct execution rate of the proposed method is 99.92%. This method can realize the reliable authentication operation among the equipment of regional substation and improve the five-prevention management level of regional substation.