The structural temperature rise and thermal stress caused by operation current and ambient temperature are some of the main factors affecting cable fatigue life. Combined with the operating and environmental conditions of the main cooling pump of the nuclear power plant, the thermal-structural coupling field numerical modeling and fatigue analysis of the 6kV single-core and three-core cable of the main pump is carried out. Based on obtaining the steady-state operating current, the motor start-up transient current, and the circulating ambient temperature, the thermal-structural coupling field numerical model of the main pump cable is established using the load transfer method to obtain the thermal and stress field distribution of the internal structural layer. The load history of one cycle is extracted for the fatigue numerical simulation of the main pump cable. The stress time history of the cable structure layer was constructed by the stress calculation results and the load time history of a single period, and the fatigue life of the main pump cable was obtained based on the S-N curve of the main insulation material and the Miner’s linear cumulative damage theory. The simulation results show that the force acting on the main pump cable by the operating current and ambient temperature is an approximately symmetric cyclic load of constant amplitude. The life cycle of the cable can reach 2.235*e4 times, and the overall life of the cable is about 63.97 years. This study can provide theoretical guidance for the safety and reliability design and state operation and maintenance of the main pump cable of the nuclear power plant.