This paper presents an overview of the geophysical activities for the seismic microzonation of 138 municipalities belonging to four Italian regions (Abruzzo, Lazio, Marche and Umbria) that were severely damaged by the seismic sequence of Central Italy (August 2016–January 2017). This study is the result of a collaborative effort between research Institutions and professional geologists with the support of local Administrations and the Italian Civil Protection Department and sets an unprecedented large-scale example of geophysical investigations supporting detailed seismic microzonation studies. This manuscript presents the methodological approach adopted for the geophysical activities, including the technical protocols and procedures, the best practices, the final products and the results supporting a detailed microzonation study of III level. The first step of the study was the collection and critical review of all available geophysical and geological information for planning the new geophysical surveys (specifically their type and location), in order to assess the subsoil geometry and the seismic characterization of the areas under investigation. Integration with the newly acquired geophysical data allowed the identification of zones with homogeneous local seismic hazard as well as the reference seismo-stratigraphy for each area, defining for each geological unit the ranges of the relevant properties in seismic amplification studies: layering and thicknesses, density, P-wave and S-wave seismic velocity. We also present a few representative case studies illustrating the geophysical investigation for different geomorphological situations. These examples, together with the findings of the entire project, are discussed to point out the strength points and the criticalities, as well as the necessary requirements in the application of geophysical methods to detailed microzonation studies.