Santé publique France carries out its activities in the regions through its Regional Directorate (DiRe) and 16 regional units (Santé publique France in the regions) attached to the regional health agencies (ARS) in mainland France and the overseas departments and regions (DROMs). Since the ministerial decree of November 28, 2016, Santé publique France also provides support to the ARS in the field of prevention and health promotion (PPS)—particularly through its regional network and its Directorate of Prevention and Health Promotion—to identify needs and target populations, select effective interventions, assist in drafting protocols, and conduct quantitative evaluations of interventions. Santé publique France contributes to the epidemiological characterization of regional population health issues, the identification of effective interventions, and the quantitative evaluation of interventions. These data and information should be supplemented by the work of various regional and national stakeholders (ORS, IREPS, local authorities, research teams, the national education system, etc.) to provide a detailed understanding of the regional context and the many determinants involved in the adoption of health-promoting behaviors. In this context, Santé publique France in the regions supports the ARS in implementing regional PPS strategies. The reality on the ground requires the ARS and Santé publique France in the regions to adapt to the complexity of each situation. Thus, the objective of this document is to propose a strategic and methodological framework for PPS for Santé publique France in the regions, based on the most frequently encountered situations, for the implementation of interventions and their evaluation. This document is a practical and methodological tool that describes the scope and procedures for Santé publique France’s regional interventions within the framework of its PPS-related missions. It does not replace existing training offerings for PPS initiation—whether through internal Santé publique France training or external courses—nor does it replace the use of existing guides and publications, which are an essential prerequisite.