Introduction: Nursing students in clinical setting are faced with various stressors that can affect their performance and clinical self-efficacy and create problems in training skilled and self-efficacious nurses. Therefore, the present study was conducted with the aim of determining the relationship between clinical self-efficacy and psychological stress in nursing students of Hamedan University of Medical Sciences in 2022. Methods: In this descriptive cross-sectional correlational study, from 350 nursing students of Hamadan University of Medical Sciences in 2022, 218 of them were selected by stratified sampling method. Data collection tools included: demographic characteristics checklist, clinical self-efficacy questionnaire and Cohen's psychological stress in clinical setting questionnaire. Data were analyzed by descriptive statistics, Pearson correlation coefficient, one-way ANOVA and independent sample t-test in SPSS. Results: According to the results, the mean ± standard deviation scores of clinical self-efficacy of students, was 65.81±11.05 and their psychological stress in clinical setting was 63.92±13.70. It was also found that there is a reverse and significant statistical relationship between clinical self-efficacy and psychological stress in clinical setting (r = - 0.25, P < 0.001). Conclusion: Clinical self-efficacy can play a significant role as a protective factor on the level of psychological stress of nursing students in clinical settings. Considering that a significant part of nursing students' learning takes place in clinical settings, paying attention to reducing students' psychological stress in these settings and subsequently improving their clinical self-efficacy is particularly important.