This study examined the role of self-esteem as a mediator in the relationships between optimism and psychological resilience on depressive symptoms in university students. A total of 494 undergraduate students, comprising of 253 female and 241 male participated in this study. Participants’ ages ranged from 18 to 30 (M = 20.85, SD = 1.57). Instruments measuring optimism, psychological resilience, self-esteem and depression were administered to university students from different faculties and departments. Application of a structural equation model to the obtained data resulted in a direct relationship between optimism and psychological resilience with symptoms of depression. In addition, it was determined that self-esteem is a full mediator between psychological resilience and depressive symptoms. The mediator role of self-esteem between optimism and depressive symptoms; however, did not reach statistically significant levels. The findings are discussed within the self-esteem, optimism, and resilience in an individual’s mental health context.