Background: Rigorous evaluations of health system interventions to strengthen hypertension and cardiovascular disease (CVD) care remain scarce in sub-Saharan Africa. This study aims to evaluate the reach, effectiveness, adoption / acceptability, implementation fidelity, cost, and sustainability of the Ghana Heart Initiative (GHI), a multicomponent supply-side intervention to improve cardiovascular health in Ghana. Methods: This study adopts a mixed- and multi-methods design comparing the effects of the GHI in 42 intervention health facilities (i.e. primary, secondary and tertiary) in the Greater Accra Region versus 56 control health facilities in the Central and Western Regions. The evaluation design is guided by the RE-AIM framework underpinned by the WHO health systems building blocks framework, integrated by the Institute of Medicine's six dimensions of health care quality: safe, effective, patient-centered, timely, effi cient, equitable. The assessment tools include: (i) a health facility survey, (ii) a healthcare provider survey assessing the knowledge, attitudes, and practices on hypertension and CVD management, (iii) a patient exit survey, (iv) an outpatient and in-patient medical record review and (v) qualitative interviews with patients and various health system stakeholders to understand the barriers and facilitators around the implementation of the GHI. In addition to primary data collection, the study also relies on secondary routine health system data, i.e., the District Health Information Management System to conduct an interrupted time series analysis using monthly counts for relevant hypertension and CVD specific indicators as outcomes. The primary outcome measures are performance of health service delivery indicators, input, process and outcome of care indicators (including screening of hypertension, newly diagnosed hypertension, prescription of guideline directed medical therapy, and satisfaction with service received and acceptability) between the intervention and control facilities. Lastly, an economic evaluation and budget impact analysis is planned to inform the nationwide scale-up of the GHI. Discussion: This study will generate policy-relevant data on the reach, effectiveness, implementation fidelity, adoption / acceptability, and sustainability of the GHI, and provide insights on the costs and budget-impacts to inform nation-wide scale-up to expand the GHI to other regions across Ghana and offer lessons to other low- and middle-income countries settings as well. RIDIE Registration Number: RIDIE-STUDY-ID-6375e5614fd49 (https://ridie.3ieimpact.org/index.php).