Infectious diseases cause psychological problems for health care workers and especially nurses. Nurses who provided coronavirus disease-2019 (COVID-19) patients with care experience negative feelings such as stress, work-related strain, discomfort, and helplessness related to their high-intensity work. The aims of this study are to investigate the effect of the mindfulness-based breathing and music therapy practice on stress, work-related strain, and psychological well-being levels of nurses who provided COVID-19 patients with care. This randomized controlled trial was conducted in a COVID-19 department at a university hospital in Turkey. Nurses who care for patients infected with COVID-19 were randomly divided into an intervention group (n = 52) and a no-treatment control group (n = 52). The intervention group received mindfulness-based breathing and music therapy. In data collection, the Personal Information Form, State Anxiety Inventory, Work-Related Strain Scale, and Psychological Well-Being Scale were used. The data from the study showed that mindfulness-based breathing and music therapy decreased stress and work-related strain (P < .05) and increased psychological well-being (P < .05). The control group showed no statistically significant changes on these measures (P > .05). The mindfulness-based breathing and music therapy practice reduced nurses' stress and work-related strain and increased psychological well-being during the COVID-19 pandemic.