First Referral Hospitals (FRHs), also known as district hospitals, play a pivotal role in both national and sub-national health systems, serving as referral hubs for smaller primary health care facilities and ensuring the delivery of essential hospital care services. Despite their recognised importance, FRHs face persistent challenges, including health workforce shortages, variation in staff skill mix, high turnover and resource constraints. These challenges are growing with increasing demands for expanded services, often driven by advances in diagnostics, therapies, health professional specialities and technologies. The AFRHiCARE study will explore longitudinally how FRHs can deploy and support healthcare workers effectively and integrate technologies to address evolving service demands. The study centres on the roles, practices and professional quality of life of different cadres of health professionals, patient experiences, and the impact of governance, leadership and management practices on health care quality and staff. We will pay special attention to how new technologies impact service delivery and reshape workforce roles and responsibilities and explore the influence of gender, location, and climate-related events. The AFRHiCARE study aims to investigate these themes in sentinel FRHs in Kenya, South Africa and Uganda, combining a longitudinal study design and mixed-methods with multiple and comparative case studies. Our overall research question is: “How can healthcare workers and technologies best be deployed and supported to provide high-quality care to all as essential hospital care evolves?” Findings will provide lessons for the design and strengthening of FRH services across sub-Saharan Africa, with relevance for other low and middle-income countries.