Background: Eating disorders (EDs) are prevalent in adolescents and young adults, leading to various psychiatric and physical complications that affect the quality of life and even mortality. Objectives: The present study aimed to investigate the mediating role of self-efficacy and self-esteem in the relationship of perfectionism and negative reactivity with EDs. Methods: This descriptive study was performed on 302 students selected from the University of Tehran during 2018-2019. The data collection tools were the ED Examination-Questionnaire Short form, Self-esteem Scale, Weight Efficacy Lifestyle Questionnaire-Short Form, ED Inventory-Perfectionism Scale, and Perth Emotional Reactivity Scale. Pearson's correlation coefficient and structural equation modeling were used to analyze the data. Results: The results showed that EDs had significant positive correlations with perfectionism (r= 0.4, P= 0.01) and general negative reactivity (r= 0.53, P= 0.01). On the other hand, these disorders had a significant negative correlation with self-esteem (r = -0.48, P= 0.01) and self-efficacy(r = 0.53, P=0.01). Self-esteem had a negative significant relationship with perfectionism (r = -0.48, P= 0.05) and negative reactivity (r = -0.68, P = 0.01). Moreover, self-efficacy had a negative significant relationship with perfectionism (r = -0.28, P = 0.01) and negative reactivity (r = -0.5, P = 0.01). The findings of path analysis showed that self-esteem and self-efficacy played mediating roles in the relationship of negative reactivity and perfectionism with EDs. Negative reactivity directly affected eating pathology (t =1.27, beta = 0.13) but is not significant. Conclusions: Our findings showed that self-esteem and self-efficacy are protective factors against the negative effects of perfectionism and negative reactivity. Therefore, self-esteem and self-efficacy can be considered as parts of prevention and treatment programs for EDs.