A control method of an operation pressure of a fuel cell system maintains a differential pressure between a hydrogen side and an air side of a fuel cell stack to minimize a crossover amount of hydrogen while allowing hydrogen purge and reduces an exhausted hydrogen amount when a purge valve is opened at the time of purging hydrogen using a differential pressure of an anode outlet and a cathode outlet to improve a hydrogen utilization rate and system efficiency. According to the control method, pressures of a cathode inlet and a cathode outlet of the fuel cell stack and a pressure of an anode outlet are controlled such that the pressure of the anode outlet of the fuel cell stack is lower than the pressure of the cathode inlet and higher than the pressure of the cathode outlet.