Background: Hospital stress is one of the most important factors in nurses’ mental health. So, this study aimed to investigate the effects of self-actualization and life orientation on hospital stress. Methods: This research was a correlational study. We analyzed the data via multiple regression and SPSS version 22. Participants included 178 female nurses from Borujerd city, Lorestan Province, Iran, selected by simple random selection method. They completed hospital stress, self-actualization, and life orientation scales. Results: Results showed that self-actualization (β=-0.29, P=0.001) and optimistic orientation (β=-0.28, P=0.001) were significant negative predictors of hospital stress, but pessimistic orientation was not a predictor. Also, the results showed that 29% of variable hospital stress was explained by the proposed model. Conclusions: According to the results of this study, increased self-actualization and optimism reduced hospital stress in female nurses.