Background Social responsibility can motivate disaster relief nurses to devote themselves to safeguarding rights and interests of people when facing challenges that threaten public health. However, few studies focused on the relationship of moral courage, job-esteem, and social responsibility among disaster relief nurses. Objective To explore the influence of moral courage and job-esteem on the social responsibility in disaster relief nurses and clarify the relationship model between them. Methods A cross-sectional study was conducted among 716 disaster relief nurses from 14 hospitals in central China through an online survey, including moral courage scale, job-esteem scale, and social responsibility questionnaire. The data were analyzed by Pearson’s correlation, and the mechanism of the effect of moral courage and job-esteem on social responsibility was completed. Ethical considerations This study was approved by the Medical Ethics Committee of the Second Xiangya Hospital of Central South University (Approval Number: 2019016). Results Disaster relief nurses’ moral courage positively impacted social responsibility (r = 0.677, p < 0.01), and moral courage could affect social responsibility through the mediating role of job-esteem. Conclusion Job-esteem mediated between moral courage and social responsibility among disaster relief nurses. Nursing managers regular assessment of nurses’ moral courage and interventions such as meetings and workshops can reduce moral distress, foster morally courageous behavior, enhance job-esteem, and improve social responsibility performance among disaster relief nurses.