Abstract Background: Coronavirus disease 2019 (COVID-19), caused by Severe acute respiratory syndrome coronavirus 2, has posed a global health crisis since its emergence in late 2019. Objectives: To assess the knowledge, attitudes, and practices related to COVID-19 prevention among medical undergraduates in Enugu Metropolis, Nigeria. Materials and Methods: A descriptive cross-sectional study was conducted, involving undergraduate medical students from the University of Nigeria, Enugu, and Ituku-Ozalla campuses. A total of 450 participants were recruited through convenience sampling, and a structured questionnaire was used for data collection. The questionnaire covered sociodemographic information, COVID-19 knowledge, attitudes, and preventive practices. Data were analyzed using the Social Package for Social Science version 28, with statistical significance set at P < 0.05. Results: The majority of participants demonstrated good knowledge of COVID-19 prevention (89.6%), with significant associations observed between knowledge and the level of study (P = 0.001). A significant relationship was also noted between knowledge and attitude (P = 0.000). In terms of practice, 24.2% of medical students reported good COVID-19 prevention practices. Additionally, a majority of participants (n = 405; 90%) had not been vaccinated against COVID-19, largely influenced by vaccine hesitancy. Conclusion: Efforts should focus on transforming knowledge into positive attitudes and encouraging better COVID-19 preventive practices among medical undergraduates. Addressing vaccine hesitancy through targeted education and awareness campaigns is imperative to mitigate the risks associated with the pandemic and potential future waves.