Background: The COVID-19 lockdown has caused increased psychological disturbances among the student community. Medical students are susceptible to mental stressors and thus more likely to be affected by the pandemic. The aim of the study was to determine the prevalence of depression, anxiety and stress in medical students during the COVID-19 lockdown in Kerala along with the associated socio-demographic factors.Methods: A web-based cross-sectional study was conducted among medical students during COVID-19 lockdown in a southern state of India. Collected data included socio-demographic details and depression, anxiety and stress scale-21 (DASS-21). Chi square test was used to determine the association of depression, anxiety and stress with the socio-demographic factors.Results: A total of 760 students were invited to partake in this study. 702 satisfied the inclusion criteria and completed the evaluation, giving a response rate of 92.4%. Among the participants 67.4% were female and 32.6% were males. Prevalence of depression, anxiety and stress among medical students were 55.1%, 33.2% and 29.4% respectively. It was found that both male and female students experienced the same levels of depression (p=0.533) during the pandemic. Students studying in private self-financing medical colleges experienced more anxiety compared to students at government medical college (p=0.008) during the pandemic. It was also observed that prevalence of depression (58.4%) was highest among first year medical students.Conclusions: The study revealed that depression, anxiety and stress were prevalent in majority of medical students during the pandemic.