An important safety factor to be considered when designing a plant is the prevention of overpressure-induced explosions, to which many plants are vulnerable because of pressurized fluids in plant components. A pilot-operated pressure relief valve is a core device for venting off overpressure formed inside vessels and pipelines. The pilot-operated pressure relief valve has a highly complicated structure, and its design and production should be thoroughly studied. In this study, a simplified structure for the pilot-operated pressure relief valve was proposed to facilitate the design and production processes, and the effective ranges of its design variables were determined to enable the prediction of the impact of the design variables in the design and production processes. The ranges determined were validated by a numerical flow analysis and experiment as follows. We calculated the maximum orifice diameter at which the main valve does not open and examined the minimum orifice diameter that can resist the impact of strong shock waves. Additionally, we defined the orifice diameter range that ensures the stable opening and closing of the main valve under various pressure conditions. The effective ranges of the design variables determined in this study can be used to ensure safe operation of a pilot-operated pressure relief valve under various pressure conditions with the design of the proposed simplified structure.