The COVID-19 pandemic provided an opportunity for office workers to experience work from home (WFH). The aims of this study are to investigate the prevalence rate of musculoskeletal discomfort (MSD) and the work conditions of homeworkers during WFH as well as to evaluate the association and predicted risk of ergonomic factors and MSD. A total of 232 homeworkers completed questionnaires. Chi-square test and logistic regression were used to analyze the association and prediction of work arrangements and home workstation setups and musculoskeletal outcomes. The result showed that 61.2% of homeworkers reported MSD while WFH. Because of the small living spaces in Hong Kong, 51% and 24.6% of homeworkers worked in living/dining areas and bedrooms, respectively, potentially affecting their work and personal life. Additionally, homeworkers adopted a flexible work style, but prolonged computer use while WFH. Homeworkers who used a chair without a backrest or a sofa could predict a significantly higher risk of MSD. The use of a laptop monitor posed about a 2 to 3 times higher risk of suffering from neck, upper back, and lower back discomfort than the use of a desktop monitor. These results provide valuable information to help regulators, employers, homeworkers, and designers create better WFH guidelines, work arrangements, and home settings.