In this study, the operation process of a γ-irradiation device, including loading, unloading, and irradiation, was simulated by the state transfer method. The effects of absorbed dose, cargo weight, loading and unloading speeds, and the dose rate of a radiation source on the whole irradiation process were studied. To enhance the irradiation efficiency and shorten the irradiation time required for combined cargo, the irradiation sequence of cargo was optimized using the genetic algorithm-traveling salesman problem (GA-TSP) algorithm. Our results showed that the proposed procedure can simulate the whole irradiation process; the radiation time can be shortened by increasing the dose rate of the radiation source in a reasonable irradiation sequence. At a source irradiation dose rate of 12 Gy/min, the simulation of 10 real incoming batches produced six dynamically optimized irradiation sequences. The time required for the sequential irradiation procedure was reduced from 13 193 min to 12 137 min, representing a reduction of approximately 8%, owing to the optimization of the irradiation sequence. This optimization significantly increases the availability of radioactive sources and improves customer satisfaction.