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Background: Out-of-pocket (OOP) payment is one of many countries' main financing options for health care. High OOP payments push them into financial catastrophe and the resultant impoverishment. The infrastructure, society, culture, economic condition, political structure, and every element of the physical and social environment influence the intensity of financial catastrophes in health expenditure. Hence, the incidence of Catastrophic Health Expenditure (CHE) must be studied more intensively, specifically from regional aspects. This systematic review aims to make a socio-ecological synthesis of the predictors of CHE. Method: We retrieved data from Scopus and Web of Science. This review followed PRISMA guidelines. The interest outcomes of the included literature were the incidence and the determinants of CHE. This review analyzed the predictors in light of the socio-ecological model. Results: Out of 1436 screened documents, fifty-one met the inclusion criteria. The selected studies were quantitative. The studies analyzed the socioeconomic determinants from the demand side, primarily focused on general health care, while few were disease-specific and focused on utilized care. The included studies analyzed the interpersonal, relational, and institutional predictors more intensively. In contrast, the community and policy-level predictors are scarce. Moreover, neither of the studies analyzed the supply-side predictors. Each CHE incidence has different reasons and different outcomes. We must go with those case-specific studies. Without the supply-side response, it is difficult to find any effective solution to combat CHE. Conclusion: Financial protection against CHE is one of the targets of sustainable development goal 3 and a tool to achieve universal health coverage. Each country has to formulate its policy and enact laws that consider its requirements to preserve health rights. That is why the community and policy-level predictors must be studied more intensively. Proper screening of the cause of CHE, especially from the perspective of the health care provider's perspective is required to identify the individual, organizational, community, and policy-level barriers in healthcare delivery. [ABSTRACT FROM AUTHOR]