Since the onset of the COVID-19 pandemic, burnout symptoms have been prevalent among healthcare workers. Living with spouses can be complex and was associated with an increased burnout risk during the COVID-19 pandemic. This study investigated the relationship between living with spouses and burnout among healthcare workers during the COVID-19 pandemic. We distributed questionnaires to participants working in a hospital affiliated with a medical university in Taiwan. The questionnaires were the Copenhagen Burnout Inventory, which comprises personal burnout (PB), work-related burnout (WB), and client burnout subscales; the Nordic Musculoskeletal Questionnaire; and information on basic demographic variables, family factors, living habits, work-related factors, and physical health factors. Multiple linear regression and mediation analysis were used. We obtained 1615 (63.81%) valid questionnaires. After analysis revealed that marriage was an independent risk factor for PB; however, the effect of marriage on WB was nonsignificant after controlling for risk factors. Parenthood, less alcohol use, reported sleep duration less than six hours, less overtime, less shift work, and participation in leisure activities with family and friends were found to be mediators between marriage and a lower WB level. In addition, chronic diseases, frequent neck pain, and shoulder pain were suppression factors. In summary, marriage was associated with an increased risk of PB. Married individuals sustain a high WB level because of changes in family roles, living conditions, and work conditions. Overall, helping healthcare workers to maintain well-being in marriage or family living may be effective in decreasing burnout during the COVID-19 pandemic.