Objective To compare strain and gender differences between ICR and C57BL/6J mouse chronic fatigue syndrome models and provide experimental evidence for the selection of model animals for chronic fatigue syndrome. Methods ICR and C57BL/6J mice (half male and half female) were injected intraperitoneally with polyinosinic polycytidylic acid (Poly I:C) every three days and forced to swim daily. The modeling was performed for 15 consecutive days, during which the weight and food intake of the mice were measured, and fatigue scores were assessed. After the modeling was completed, behavioral tests were carried out, including exhaustive swimming, tail suspension, mechanical pain threshold, and elevated plus maze. Results Compared with the control group, both strains of model mice had significantly decreased exhaustion times in the exhaustive swimming test(P<0. 05,P<0. 01), significantly increased immobility time in the tail suspension test(P<0.05,P<0.01), and a significantly decreased mechanical pain threshold(P<0.05,P<0.01), and male model mice had significantly decreased open arm entry time and frequency in the elevated plus maze(P<0.05,P<0.01). The weight of model male C57BL/6J mice significantly decreased(P<0.05,P<0.01). The weight of model female ICR mice increased after a significant reduction(P<0.05). The exhaustion time of control C57BL/6J mice was significantly lower than that of control ICR mice(P<0.01). The immobility time of model C57BL/6J mice was significantly greater than that of model ICR mice(P<0.01). Conclusions There were differences between the two strains of mice in terms of weight change, fatigue level, and depression. Within the same strain, there were differences between males and females, and the anxiety level of males was higher than that of females.