Background: Depression among medical students may promote development of physical and mental problems. Few studies investigated its prevalence among medical students in Egypt. Objective: This study aimed to determine the prevalence of depression and to identify some related risk factors among Al-Azhar University medical students, Cairo, Egypt. Subjects and Methods: A cross-sectional study was conducted at Faculty of Medicine (Boys and Girls), Al-Azhar University, Cairo, Egypt. A cluster sample was taken and included students from all study years. A self-administered questionnaire was completed to 1254 students from January to March 2017. Data concerning socio-demographic and lifestyle and sleeping related factors were collected using a valid self-administered structured questionnaire including PQ-2 instrument for depression screening. The prevalence of depression was estimated, and appropriate statistical analyses were performed to compare the prevalence of depression by the studied students' factors. Results: The overall prevalence of depression was 42.9%. The prevalence was significantly high among females (46.4%), early study years (48.4%), and those living away from family. Students reported frequent fast food intake, watching TV and use social media, not in touch with their friends, and those eating one meal per day also showed significant high prevalence. Sleeping related factors appeared to influence the prevalence of depression among the studied students where prevalence was high among those reported less sleeping hours, use of sleeping medications and those spent > 2 hours in bed before sleeping. Conclusion: A high prevalence of depression among the studied medical students was detected. The study suggested a variety of risk factors and the need of psychiatric counseling and support services available to vulnerable students.