Background: Academic self-efficacy is an important prerequisite for academic achievement of students. This study aimed to determine the association between happiness and spiritual health with academic self-efficacy among students of Guilan University of Medical Sciences (GUMS), Iran. Methods: Using quota sampling method, 250 students studying at different filed of medical sciences at GUMS were selected. The Oxford Happiness Questionnaire, Ellison and Paloutzin spiritual well-being scale, and Owen & Froman’ s Academic Self-Efficacy Questionnaires were used to measure happiness, spiritual health, and self-efficacy, respectively. Data were analyzed using t-test, analysis of variance, and multivariate linear regression model in Stata version 14. Results: The mean score of happiness, spiritual health, and self-efficacy was 68. 7 (SD = 13. 2), 84. 7 (SD = 17. 3), and 96. 7 (SD = 15. 9), respectively. there was moderate significant correlation between happiness with spiritual health (r = 0. 59, P-value = 0. 001) and self-efficacy (r = 0. 58, P-value = 0. 001). Spiritual health and self-efficacy had a weak correlation (r = 0. 28, P-value = 0. 001). Linear regression analysis showed that happiness was independently associated with self-efficacy. The mean score of self-efficacy increased by 0. 75 per unit of increase in the happiness score (P-value = 0. 001). Conclusion: This study revealed a moderate level of happiness and self-efficacy among students of Guilan University of Medical sciences. Happiness was the only significant predictor of self-efficacy.