Abstract: Aiming at the pandemic control as a complex interactive relationship problem with high uncertainty and usually involving a large number of decision makers, this study integrates grey theory, large-scale group decision-making and DEMATEL method to innovatively propose a new large-scale group Grey-DEMATEL decision framework, which can examine the interdependence of relationships and system components. The framework mainly uses the grey relational clustering method to cluster large-scale group decision makers, so as to gather the decision makers’ evaluation information on factors and construct the relevant DEMATEL matrix to extract the key factors. In addition, under the proposed framework, a detailed inspection of the actual situation in Ghana was carried out. Through a comprehensive review of relevant literature and the actual situation in the country, a series of factors that affect the detection and control of COVID-19 have been identified and explained. Then use the proposed decision-making framework to extract the key factors, which are formally listed as priorities, so that policymakers can invest scarce resources. The results of detailed case studies and policy recommendations on the situation in Ghana prove the effectiveness of this novel approach.