Objective To investigate the influencing factors and mediating effects of psychological resilience,occupational burnout,job well-being,and social support among clinical nurses,providing a theoretical basis for improving job well-being,optimizing the nursing work environment,and developing effective intervention measures. Methods A random sampling method was used to select clinical nurses from 7 grade-A tertiary general hospitals in Shanghai from June to December 2023 as the research subjects. Questionnaires were administered using the psychological resilience scale,social support scale,job well-being scale,and occupational burnout scale,and the influencing factors and mediating effects of psychological resilience,social support,job well-being,and occupational burnout were analyzed. Results A total of 1 174 valid questionnaires were collected. The psychological resilience score of clinical nurses in grade-A tertiary general hospitals in Shanghai was (28.45±0.67)points,the social support score was (53.59±0.73)points,the job well-being score was (23.34±0.46)points,and the occupational burnout score was (47.22±0.40)points. The differences in psychological resilience scores among clinical nurses with different educational backgrounds and professional titles were statistically significant(both P<0.05). The differences in job burnout scores among clinical nurses with different genders,ages,educational backgrounds,and professional titles were statistically significant(all P<0.05). The differences in job well-being and social support scores among clinical nurses with different ages,educational backgrounds,and professional titles were statistically significant(all P<0.05). The psychological resilience of clinical nursing staff was negatively correlated with job burnout(r=-0.607,P<0.01),and positively correlated with job well-being and social support(r=0.712,0.623,both P<0.01). Job burnout was negatively correlated with both job well-being and social support(r=-0.693,-0.717,both P<0.01),while job well-being was positively correlated with social support(r=-0.682,P<0.01). The non-standardized total effect of psychological resilience on work well-being was 0.698,with a direct effect of 0.299. The mediating effects of job burnout and social support were 0.207 and 0.192, accounting for 29.656% and 27.507% of the total effect, respectively, with 95%CI not including 0. Conclusion Job burnout and social support play partial mediating roles in the association between psychological resilience and work well-being. Nursing managers should simultaneously address job burnout mitigation and social support enhancement to promote the work well-being of clinical nursing staff.