Floods, at present, may constitute the natural phenomenon with the greatest impact on the deterioration of cultural heritage, which is the reason why the study of flood risk becomes essential in any attempt to manage cultural heritage (archaeological sites, historic buildings, artworks, etc.) This management of cultural heritage is complicated when it is distributed over a wide territory. This is precisely the situation in the region of Castile and León (Spain), in which 2155 cultural heritage elements are registered in the Catalog of Cultural Heritage Sites of Castile and León, and these are distributed along the 94,226 km2 of this region. Given this scenario, the present study proposes a methodological framework of flood risk analysis for these cultural heritage sites and elements. This assessment is based on two main processing tools to be developed in addition: on the one hand, the creation of a GIS database in which to establish the spatial relationship between the cultural heritage elements and the flow-prone areas for different flood return periods and, on the other hand, the creation of a risk matrix in which different variables are regarded as associated both to flood hazard (return period, flow depth, and river flooding typology) and to flood vulnerability (construction typology, and construction structural relationship with the hydraulic environment). The combination of both tools has allowed us to establish each cultural heritage flood risk level, making its categorization of risk possible. Of all the cultural heritage sites considered, 18 of them are categorized under an Extreme flood risk level; and another 24 show a High potential flood risk level. Therefore, these are about 25% to 30% of all cultural heritage sites in Castile and León. This flood risk categorization, with a scientific basis of the cultural heritage sites at risk, makes it possible to define territories of high flood risk clustering; where local scale analyses for mitigation measures against flood risk are necessary.