The novel Coronavirus pandemic caused strong negative emotions including fear, and stress and impacted the mental health of individuals worldwide. One of the emotions linked with mental health and infectious disease is self-blame regret. Thus, the current study investigated the role of fear of COVID-19 and perceived stress in the relationship between self-blame regret and depression. As a means of such investigation, the current research was conducted based on quantitative data and the research sample was recruited via a convenient sampling method. A community sample of 352 individuals in Turkey (71% female and 29% males), ranged between in age 18 and 63 (M= 28.90±8.90), completed Fear of COVID-19 Scale (FCV-19S), Perceived Stress Scale (PSS-10), Depression, Anxiety, and Stress Scale (DASS-21), and responded to one item concerning the self-blame regret. Results demonstrated that self-blame regret is positively correlated with fear of COVID-19, perceived stress, and depressive symptoms. Moreover, serial multiple mediation analyses demonstrated that both fear of COVID-19 and perceived stress mediated the relationship between self-blame regret and depression. The findings showed that self-blame regret, fear of COVID-19, and perceived stress are determinants of depressive symptoms, suggesting that such factors are important in understanding these issues.