From January to April 2020, the COVID-19 pandemic affected eastern China, leading medical students to adopt home protection measures that significantly altered their physical activity and lifestyle habits. This study aimed to assess the prevalence of musculoskeletal pain (MSP) among medical students during home protection and to analyze the influence of demographic factors, physical exercise habits during normal school life, home protection data on MSP. This research provides a foundation for developing interventions to reduce MSP among medical students. A cross-sectional survey was conducted at Nanjing Medical University in Jiangsu Province from January to April 2020, utilizing the Nordic Musculoskeletal Questionnaire (NMQ) to measure MSP. Multivariate logistic regression identified factors influencing MSP. A total of 859 students participated, with a 40.2% prevalence of MSP during home protection. Multivariate analysis showed that female sex (OR: 1.648; 95% CI: 1.157-2.347), irregular physical exercise during school (OR: 1.648; 95% CI: 1.157-2.347), and less than or equal to six hours of sleep per day during home protection (OR: 1.474; 95% CI: 1.020-2.131) were significant risk factors. The high prevalence of MSP underscores the need for interventions that focus on gender-specific risks, promote regular physical exercise, and ensure adequate sleep.