Regionalization is the integrated organization of a healthcare system, wherein regional structures are responsible for providing and administrating health services in a specific region. This method was adopted by several countries to improve the quality of provided care and to properly utilize available resources. Thus, a systematic review was conducted to verify effective interventions to improve health and management indicators within the health services regionalization. The protocol was registered in PROSPERO (CRD42016042314). We performed a systematic search in databases during February and March 2017 which was updated in October 2020. There was no language or date restriction. We included experimental and observational studies with interventions focused on regionalization-related actions, measures or policies aimed at decentralizing and organizing health offerings, rationalizing scarce capital and human resources, coordinating health services. A methodological assessment of the studies was performed using instruments from the Joanna Briggs Institute and GRADE was also used to assess outcomes. Thirty-nine articles fulfilled the eligibility criteria and sixteen interventions were identified that indicated different degrees of recommendations for improving the management of health system regionalization. The results showed that regionalization was effective under administrative decentralization and for rationalization of resources. The most investigated intervention was the strategy of concentrating procedures in high-volume hospitals, which showed positive outcomes, especially with the reduction of hospitalization days and in-hospital mortality rates. When implementing regionalization, it must be noted that it involves changes in current standards of health practice and in the distribution of health resources, especially for specialized services.