The emergence of Coronavirus disease 2019 (COVID-19) pandemic forced the Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM) to ensure the transition from face-to-face learning to online teaching for continuity of education. This study aimed to investigate the association between e-learning and mental health status of UKM medical students. A cross-sectional study was carried out among Years 4 and 5 UKM medical students. Participants were randomly selected from a registered list. Students’ perceptions of e-learning usage prior to and during COVID-19 pandemic and its relation to mental health status were assessed using The World Health Organisation Quality of Life (WHOQOL-BREF) and Hospital Anxiety and Depression Scale (HADS) questionnaires. Mean scores for depression were 5.35 (SD 3.38) and anxiety 6.48 (SD 3.36). The frequency of e-learning usage per week was increased during COVID-19 compared to pre-COVID period (p=0.045). Comparing the four domains of quality od life (QOL), psychological health had the lowest mean score of 62.63 (SD 15.22) while the environmental domain was the highest 69.34 (SD 10.92). Total QOL scores were significantly correlated with depression (p<0.001) and anxiety (p<0.001). This study provided insights into the effect of e-learning practice on medical students’ mental health status. A significant increase in e-learning usage during COVID-19 was observed.