Sense of humor constitutes a part of everyday life and work and an indispensable part of healthcare. However, the relationship between sense of humor and nursing occupational health and stress is yet to be studied in Iran. This study aimed to analyze the interplay of demographic factors, occupational stress, sense of humor, and health status of nurses working at the hospitals affiliated with the Ahvaz Jundishapur University of Medical Sciences, Iran. In this descriptive-analytical study, the statistical population consisted of 203 nurses. Occupational stress was assessed using the Iranian version of the Effort-Reward-Imbalance (ERI) Questionnaire. The Sense of Humor Questionnaire (SHQ) and the Iranian version of the 12-item General Health Questionnaire (GHQ-12) were employed to assess the sense of humor and physio-psychological health, respectively. Data collected were analyzed using the Statistical Package for the Social Sciences (SPSS) software. 81% (n=164) of the participants had an “external effort” (E) and “reward” (R) ratio greater than 1, indicating very high occupational stress. 39% (n=79) nurses with high occupational stress displayed their commitment to the workplace. Approximately 42% (n=85) of nurses were suffering from health problems. The mean humor score of participants was 2.90±0.41. Major life events over the past 3 months (p<0.01), weekly working hours (p<0.01), high occupational stress (p<0.01), and sense of humor (p<0.01) were determined to be significant predictors of nurses' health problems. Decision-makers are recommended to reduce nursing working hours through work shift management in order to maintain nurses' health status and reduce their occupational stress. In addition, hospital directors should promote a sense of humor in hospital environments with the help of culture-building practices, comedy books, music CDs, and training courses.