Background: Evidence for the effectiveness of interventions aimed at improving the health-related quality of life of people living with cancer and/or family members is compelling. However, most interventional research has been conducted in high-income countries, and no intervention had been tested in low-income countries such as Nigeria. It is critical to design a culturally theory-based intervention in a resource-poor setting to address the needs and support coping strategies of cancer patients and their family caregivers. Methods: Theory, evidence, and practical issues were considered. The Medical Research Council framework for developing and evaluating complex interventions and Behaviour Change Wheel provided the framework for intervention design. Findings generated by a needs assessment of adult Nigerians with cancer and their family caregivers and relevant theories (the Spirituality and the Supportive Care Framework for Cancer) informed content development. Results: A theory-based, culturally tailored socio-spiritual intervention was developed to address the specific needs of adult Nigerians with cancer and their family caregivers. A 4-week intervention included strategies designed to improve social and spiritual support, information and health literacy, and health-related quality of life. Conclusions: A systemic approach was used to conceptualise an evidence-based and theory-informed intervention tailored to address previously identified shortfalls in support available to adults living with cancer and their family caregivers, in Nigeria. If implemented and effective, such an intervention has the potential to improve the health-related quality of life of people living with cancer and their families in Nigeria.