Purpose This study identified the mediating effect of resilience on the relationship between job stress and the professional quality of life of hospice and palliative care nurses. Methods The participants included 136 hospice and palliative care nurses from 13 inpatient hospice and palliative care wards at a tertiary hospital in a metropolitan city in South Korea. Data were collected from February 2022 to March 2022. Hayes' PROCESS macro 3.5 was used to test the significance of the parameter's indirect effects. Professional quality of life was divided into three subdomains: compassion satisfaction, secondary traumatic stress, and burnout. Results As a mediator, resilience had both direct and indirect effects on the relationship between job stress and the compassion satisfaction of hospice and palliative care nurses. Furthermore, there were both direct and indirect effects on the relationship between job stress and secondary traumatic stress. Finally, although there was no direct effect on the relationship between job stress and burnout, there was an indirect mediating effect. Conclusion This study confirmed the direct effect of compassion satisfaction on job stress and the professional quality of life of hospice and palliative care nurses, as well as the mediating effect of resilience on job stress and burnout. To improve the professional quality of life of hospice and palliative care nurses, it is necessary to develop and apply programs that enhance resilience in order to promote its mediating effects on compassion satisfaction and burnout.