Previous investigations have indicated potential associations between dedicated quarantine and depression. However, a literature gap exists regarding the impact of home quarantine on mental status. Accordingly, our study aims to estimate the psychological effect of home quarantine on university students in Iraq, Jordan and Syria. Our study was conducted via an online survey of 4955 randomly selected university students from 123 universities in Iraq, Jordan and Syria. Our survey included questions regarding sociodemographic characteristics along with the validated Arabic version of the CES-D (The Centre for Epidemiologic Studies Depression Scale) to assess the risk and prevalence of depressive symptoms. Among respondents, 73.2% were women, 89.9% were aged between 17 and 24 years and 65.5% were studying medical specialties. The mean CES-D score was 25.57 ± 12.6. The CES-D score was greater than 16 for 75.8% of quarantined persons, a typically recommended cut-off to identify patients at risk of clinical depression. Risk factors for depression were studying in Iraq, being female, being of a younger age, smoking, having a low and middle income, partial adherence to home quarantine rules and living alone or with a person taking immunosuppressants (p < .05). A high prevalence of clinical depression was observed among university students during the COVID-19 home quarantine. The evidence from this study suggests that post-quarantine psychological interventions are needed; governments should focus on providing psychological services to those in need in the aftermath of the COVID-19 pandemic and addressing psychological aspects while preparing for future pandemics.