Mental health disorders, including depression, cause more than half of worldwide disabilities. We aimed to estimate the prevalence of depression and determine its associated factors among Egyptian public servants. We collected data from 3134 subjects (1619 females and 1515 males) via a self-administered questionnaire, including the Center of Epidemiological Studies-Depression (CES-D) scale, medical history, sociodemographic, familial, occupational, and behavioral characteristics of the recruited Egyptian Public servants. We used logistic and linear regression models to assess the determinants of depression. The prevalence of depression was 43.5% (52.9% in females and 33.4% in males) among public servants. The past history of depression was a significant determining factor of depression; adjusted odds ratio (aOR): 95% confidence interval (CI) was 2.58 (1.87, 3.57) in females and 3.28 (2.20, 4.87) in males. Other determinants were daily working hours: aOR = 1.11 (1.02, 1.19) and high job demands: aOR = 2.19 (1.40–3.41) in males, and the high job control in females: aOR = 0.51 (0.36, 0.73). With the past history of depression, job demands, job control, family structure, education level, and working status of the spouse predicted 41% of the total variance in the CES-D score in females; R2 = 0.41; whereas job demands, family structure, job hours per day predicted 40% of in males; R2 = 0.40. In conclusion, the determinants of depression varied by gender. Governmental interventions aiming to improve the work environment (job demands, control, and working hours) and individual responsibilities to improve the living arrangement and education level could help to curb the emerging risk of depression.