Winding wire, as an important part of electrical equipment such as motor coils, is vital to the stable operation of reactor electrical equipment. The insulation aging of winding wire in reactor environment is affected by multiple factors such as temperature, voltage and irradiation. Due to the complex aging mechanism under the effect of multi-factor coupling, it has become a research hotspot to explore the influence of single factor and multi-factor coupling on the insulation lifespan of winding wire, and give the insulation lifespan of winding wire under multiple factors. In this paper, design of experiment (DOE) method was used to test design and results analysis, and the corona resistance tests of winding wire were carried out to get the corona resistance lifespans, which were regarded as the insulation indicator of winding wire under multiples factors. Full factorial experimental design was planned by changing the temperature, irradiation dose, and voltage amplitude at two level. The corona resistance lifespans of the samples were obtained, and the data were processed by the two-parameter Weibull distribution. Finally, the effects of single-factor and multi-factor coupling on insulation lifespan were discussed, and a model for evaluating the insulation lifespan of winding wire under the combined effects of three parameters was developed.