This study aims to assess the prevalence of depression and anxiety during the COVID-19 outbreak embedded within the war in Syria. A web-based cross-sectional survey design was employed. The 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder scale revealed a high prevalence of depressive (n = 3326; 83.4%) and anxiety symptoms (n = 2777; 69.6%) among the 3989 participants. Multivariable logistic regression analysis was performed to identify factors associated with depression and anxiety. There is an urgent need within the healthcare system in Syria to provide mental healthcare to alleviate acute mental health disturbances and associated physical health perceptions among Syrians.