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Depression is a widespread mental health disorder affecting more than 264 million people globally. This cross-sectional study assessed the knowledge and preventive practices related to depression among 279 undergraduate medical students at a tertiary institution in Benin City, Nigeria. The majority (73%) of the sample were young adults aged 18-24 years old. Most participants were female (65%), single (88%), and identified as Christian (92%). Overall, 54.5% of students demonstrated good foundational knowledge about depression as a prevalent mental health issue that can lead to suicide. However, critical knowledge gaps existed regarding the diagnostic criteria for depression. Only 49.1% correctly identified key symptoms like changes in appetite and sleep. Additionally, just 38% recognized the role of genetics and family history as risk factors. Regarding preventive practices, 68% of students reported engaging in positive behaviours like maintaining strong social connections, exercising regularly, and avoiding drug/alcohol abuse. Still, 32% were found to have poor preventive practices, underscoring the need for improvement. Perceived confidence in recognizing signs and symptoms of depression was high for 69% of respondents but low for 31%. In conclusion, this study provides valuable insights into the knowledge and preventive practices of depression among undergraduate medical students. The findings emphasize the need for targeted education and support to bridge the gaps in understanding and promote effective preventive measures. The researcher therefore recommends that efforts should be made to enhance the confidence of students in recognizing signs and symptoms of depression and training programs for faculty and staff to effectively identify and support students with mental health issues, ultimately promoting mental health awareness within the institution.