Abstract Background During any critical health care situation as COVID-19 pandemic, it is expected that the medical staff will be under a high level of stress. However, nurses specifically are under both physical and psychological pressure during this pandemic, with a risk of mental health problems, such as anxiety and depression. Accordingly, nurses exposed to patients with COVID-19 infection are expected to suffer from a high level of depressive symptoms. This cross-sectional study was applied on 456 nurses with age ranges from 18 to 60. They were divided into two groups: group 1 were composed of 228 nurses who were directly exposed to suspected or confirmed cases of COVID-19 patients, while group 2 were composed of 228 who were less exposed to suspected or confirmed cases of COVID-19 patients for comparison. Data were collected by personal interviews with nurses using Patient Health Questionnaire 9 (PHQ 9) scale for assessment of presence of depressive symptoms and its severity. We aimed to assess the both the prevalence and the predictors of depressive symptoms among nurses exposed to COVID-19 patients. Results We found a statistically significant higher percentage of depressive symptoms among nurses directly exposed to COVID-19 patients (61.8%) versus the less exposed group (18%). There was a statistically and significantly higher specific COVID-19 associated stressors score (SCAS) among nurses directly exposed to suspected or confirmed cases of COVID-19 patients compared to those who were less exposed; likewise, the PHQ-9 score was a statistically and significantly higher among directly exposed group compared to less-exposed group. Moderate and severe depressive symptoms were present in 23.2% and 22.4%, respectively, within the group of nurses with direct exposure; meanwhile, the less-exposed group showed 7.5% and 3.9%, respectively, with statistically higher significant difference. On doing a linear regression analysis, all the following predictors were significantly independently associated with higher PHQ-9 scores (with higher depressive symptoms severity) among nurses exposed to COVID-19: physical isolation (restrictions on touching others, even after working hours), exposure to a new COVID-19 patient, developing COVID-19-like symptoms, displaying COVID-19-like symptoms by colleagues, knowing that COVID mortality rate exceeds influenza, possible separation from family, concern about family members, fears about infection for patients, family, and friends. Conclusions COVID-19 pandemic has serious effects on the psychological well-being of nurses exposed to COVID-19 patients. There was an increased rate of depressive symptoms among them during the pandemic with its subsequent burden. Therefore, nurses exposed to COVID-19 patients are in a high need of care and support during the pandemic