Background: The global spread of COVID-19 has increased medical students' anxiety and depression. In order to contain the pandemic, isolation techniques, and social separation have been implemented. Aim of the study: was to assess the prevalence rates of anxiety and depression among medical students within the ongoing of pandemic, and to determine risk factors that predict changes in their mental health status. Methods: A cross-sectional study was conducted among 500 undergraduate medical students in Kafrelshiekh University during the pandemic. A pre-designed questionnaire that included socio-demographic data, perception of the general state of health, personal and family experience with COVID-19 infection, and the hospital anxiety and depression scale. Results: A total of 500 participants, of which 49.6% were males and 50.4% were females. 46.8% of the participants experienced symptoms related to mild anxiety, whereas 9.6% reported signs of moderate to severe anxiety. Concerning depression, 38.0% of individuals reported experiencing mild symptoms, while 11.4% reported experiencing moderate to severe symptoms. Female preclinical students who perceived themselves as having health difficulties or prior mental health issues were shown to be at a greater risk for elevated anxiety and depression scores (p < 0.05). There was no significant correlation seen between prior self-infection or infection among family members with COVID-19 and the occurrence of sadness or anxiety. Conclusion: The COVID-19 pandemic has negatively impacted the mental health of undergraduate medical students, increasing anxiety and depression levels. Personal factors like pre-existing conditions and academic stress contribute to this.