Background Sepsis accounts for approximately 11 million deaths annually worldwide, with sub-Saharan Africa bearing a disproportionate burden. Despite high sepsis mortality, limited data exist on sepsis management in African emergency and critical care settings. In Ghana, adult sepsis care is poorly characterised, and there are currently no national sepsis management protocols. Hospitals face significant resource constraints including inconsistent access to diagnostics and critical care infrastructure and delays due to out-of-pocket payment requirements, yet the extent to which these constraints affect patient outcomes remains poorly characterised. This study aims to characterise sepsis presentation and severity, early management practices, and resource-related barriers in Ghanaian emergency and critical care settings. Methods This mixed-methods, multicentre observational cohort study will be conducted across two emergency departments and two ICUs at two major referral hospitals in Accra, Ghana. The quantitative component will include approximately 385 adult patients (≥18 years) with suspected or confirmed sepsis over six months, and clinical data will be abstracted from medical records using standardised electronic case report forms. The primary outcome is the proportion of patients receiving at least partial Sepsis Six bundle compliance, defined as receipt of antibiotics, fluids, and cultures within six hours. Secondary outcomes include sepsis severity, qSOFA-based risk stratification, timing of individual bundle components, resource availability, and patient outcomes including mortality and length of stay. Semi-structured interviews with 16 clinicians will explore how resource availability shapes clinical decision-making. Quantitative data will be analysed using descriptive statistics and multivariable regression models, while qualitative data will undergo thematic analysis. Discussion This study will generate the first multicentre evidence base on early sepsis management practices in Ghanaian emergency and critical care settings. Findings will inform context-adapted national sepsis guidelines, support quality improvement initiatives, and guide future implementation research to reduce preventable sepsis mortality in Ghana and comparable resource-limited settings.