The issue of effectiveness in healthcare plays a role in international debates. The search for adequate tools allowing management to evaluate the correct allocation of resources becomes increasingly necessary. Cost-effectiveness analysis responds to this need, but the variety of tools and solutions proposed makes their application and replicability complex. The aim of this study was to create a starting approach model useful to researchers and professionals to cost-effectiveness problem solving. The study integrates two approaches by unifying the PRISMA-Compliant Systematic Literature Review and Bibliometric Analysis. The results obtained from the analysis are manifold. Scientific production related to cost-effectiveness in healthcare has increased in the last ten years and is mainly concentrated in three sources. Researchers insert multiple keywords into the articles, but the main ones are cost effectiveness analysis, human, health care cost. The topics covered can be divided into two clusters, which can be further divided into several subgroups. PRISMA analysis reinforces and confirms what has been identified through bibliometric analysis: in cost-effectiveness analysis different methodological bases are applicable to specific individual topics; in particular, the most used approaches to evaluate cost-effectiveness are DES (discrete event simulation) and Mathematical-statistical analysis methodologies, whose applications need the highlighted data. The study also underlines the literature absence of some specific topics such as spillover from primary and secondary health prevention activities, organization of services, rehabilitation activities, centralization of services related to contracts and PPPs, evaluation of infra-hospital care pathways.