<p>Patients living with cancer and their families experience several challenges that affect their health-related quality of life (HRQOL). Perceived factors affecting the quality of life (QOL) among patients living with cancer have rarely been studied. We aimed to explore the factors perceived to be associated with health-related quality of life among patients living with cancer attending a National Cancer Centre at Kamuzu Central Hospital in Malawi. Between May and June 2022, we conducted a qualitative study to assess perceptions and lived experiences of patients living with cancer, their caregivers, and healthcare workers working at the cancer centre on health-related quality of life. We purposively selected and interviewed thirteen participants. Interviews were transcribed, coded using NVivo 12, and analyzed using thematic analysis. Two broad categories of emerging themes of quality of life were identified. These included: (a) individual-level factors such as experiences with diagnosis and treatment, changes in physical, psychological, and social health, support received, benefits, and challenges, (b) facility-level factors such as availability of resources, relationship with providers, satisfaction with cancer care, facility organization, facilitators and barriers to improved quality of life. This study has highlighted the importance of physical, psychological, and social factors as key determinants perceived to be affecting health-related quality of life among patients living with cancer and their caregivers at the National Cancer Centre, Kamuzu Central Hospital in Malawi. The QOL challenges experienced by patients and their caregivers indicated that cancer care interventions should consider a holistic approach to cover all dimensions of life in order to improve health-related quality of life among patients living with cancer.</p>