Objectives: To analyze the influence of change fatigue on clinical nurses’ turnover intention, and explore the mediating roles of emotional exhaustion and job satisfaction, so as to provide references for reducing nurses’ turnover intention. Methods: From October to December 2025, a questionnaire survey was conducted among 281 clinical nurses in a Grade A tertiary hospital in Foshan using a general information questionnaire as well as scales of change fatigue, job burnout, job satisfaction, and turnover intention. Pearson correlation and multiple linear regression analyses were adopted to analyze variable relationships, and the Bootstrap method was used to test mediating effects. Results: Change fatigue and emotional exhaustion were positively correlated with turnover intention (r = 0.429, 0.523, p < 0.01), while turnover intention was negatively correlated with job satisfaction (r = -0.429, p < 0.01). All three variables were important predictors of turnover intention, among which emotional exhaustion exerted the greatest impact. Emotional exhaustion and job satisfaction played significant partial mediating roles between change fatigue and turnover intention, with the total indirect effect accounting for 60.86%. Moreover, a chain mediating path of “change fatigue à emotional exhaustion à job satisfaction à turnover intention” was verified. Conclusion: Change can directly affect clinical nurses’ turnover intention, and also exert an indirect impact through the above mediating pathways. Nursing managers should pay attention to nurses’ psychological adaptation during organizational changes. By alleviating change fatigue, relieving emotional exhaustion, and improving job satisfaction, turnover intention can be reduced, and the nursing workforce stabilized.