Payment methods based on a controlled or adjusted prospective payment system rather than ‘Fee for Services’ or direct payment are considered beneficial to access the healthcare delivery services. The purpose of this review was to identify technical challenges faced by three WHO regions, namely, Western Pacific, South East Asia Eastern and the Mediterranean while establishing or adopting a diagnosis-related group (DRG)/case-mix grouper and report the extent of implementing this system for reimbursement and healthcare financing in three WHO regions, namely, Western Pacific, South East Asia Eastern and the Mediterranean. The study followed PRISMA guidelines, and 33 articles published from 1st January 2009 to 31st December 2019 were selected for critical appraisal after systematic filtration. The objectives of the implementation of the DRG system in most developed and developing countries in these regions were to bring transparency in the payment system and reduce treatment costs by avoiding unnecessary healthcare services. The countries in the study regions were at different levels of economic and social development status, therefore the implementation and adaptation status of DRG/case-mix system/grouper varied in these countries The findings revealed that most of the countries faced challenges related to inequalities and inefficiencies in the healthcare system, shortage of funding, poor documentation related to diagnosis and procedures, incomplete medical record files and lack of primary data required for the case-mix system during the DRG/case-mix adaptation phase. The results also pointed to the importance of initial pilot testing of the DRG/case-mix system/grouper and careful manipulation and adaptation to the local context, especially when the DRG system/grouper imported from other countries.