Protected Designation of Origin (PDO) cheeses are generally considered as high quality, non-standardised fermented products whose sensory richness arises from a variety of milk production and processing conditions. These practices would contribute to shaping microbial communities that have adapted to the dairy environment. In this most comprehensive study ever conducted on French PDO cheeses, our objective was to characterise the drivers of microbial communities in milks and the associated cheeses, and their relationships to biogeography, herd management and cheese processing practices. Thanks to the contribution of PDO cheese stakeholders, we sampled 1,145 PDO cheeses (each for rind and core) and 390 milks covering the diversity of the 44 French ripened PDO cheeses and collected detailed data on their production conditions. We characterised the bacterial and fungal communities of milks and cheeses using 16S rRNA and ITS2 gene sequencing. A total of 1,230 bacterial species and 1,367 fungal species were identified from the milk samples, with variations according to the dairy species. A total of 820 bacterial species and 333 fungal species were identified in cheeses. The core microbiome in cheese was limited to one fungal species (Geotrichum candidum) at 100% prevalence. The cheese’s microbiota differed in terms of richness and composition between the seven cheese families and within families, according to PDO labels. Secondary structuring factors, as the dairy species, the geographical area and cheese ripening practices, were also highlighted across cheese families, demonstrating a contribution of biogeography and PDO-specific know-how in shaping the cheese microbiota.