Background: Nursing is associated with many stressful situations that can cause problems such as fatigue, reduced quantity and quality of patient care, as well as physical and mental illness. Safety climate is one of the most important indicators of safety management performance that evaluates employees' attitudes toward safety issues. Objectives: This study aimed to investigate the association between safety climate and occupational fatigue in nurses. Methods: This descriptive-analytical study was performed on nurses working in hospitals affiliated with Shahrekord University of Medical Sciences in 2018. We selected 216 nurses by a proportional quota sampling method. A demographic questionnaire, the nurses' safety climate questionnaire designed by the USA, and the occupational fatigue questionnaire designed by Sweden were used to collect information. The validity and reliability of the questionnaires were confirmed. Statistical tests for two independent samples, analysis of variance, Mann-Whitney, Kruskal-Wallis, and multiple regression analysis were used to analyze the data by SPSS version 21 software. Results: The results showed that the mean scores of occupational fatigue and safety climate were 72.23 ± 7.75 and 3.46 ± 0.305, respectively, and 72.23% of nurses reported occupational fatigue. There was no significant relationship between safety climate and the education level, gender, and job satisfaction (P < 0.05). Also, there was no significant relationship between occupational fatigue and job satisfaction and education (P < 0.05), but there was a significant relationship between job satisfaction and gender, age, and marital status (P < 0.05). Having a second job by nurses increased their occupational fatigue by 19%. The effect of safety climate on occupational fatigue was about -0.09. Conclusions: The findings of this study showed that demographic variables have significant effects on occupational fatigue, and increasing the safety climate can reduce employees’ occupational fatigue.