High levels of disinfection by-products (DBPs) are constantly found in drinking water distributed in Sardinia, an Italian island with a tourist vocation and critical issues related to the drinking water supply. To reduce the concentration of trihalomethanes the disinfectant in use was changed – chlorine dioxide was adopted instead of hypochlorite. However, this caused the appearance of other DBPs (e.g., chlorites) in water distributed to the population. Thus, the use of monochloramine as a secondary disinfectant (associated with chlorine dioxide as the primary disinfectant) was evaluated in four drinking water treatment plants supplied by artificial basins located in the central-northern part of Sardinia. Raw, disinfected and distributed waters were studied for genotoxicity using a battery of in vitro tests on different cells (bacteria, plant and mammalian cells) to detect different genetic endpoints (i.e., point and chromosome mutations and DNA damage). Moreover, a chemical and microbiological characterisation of water samples was performed. All samples of water distributed to the people showed mutagenic or genotoxic effects in different cells/organisms. In particular, chromosome aberrations in plant cells and DNA damage in human cells were observed. In this study, the use of chloramines associated with other disinfectants did not eliminate the mutagenicity present in the raw water and when the raw water was not mutagenic it introduced mutagenic/genotoxic substances. A careful management of drinking water is needed to reduce health hazards associated with the mutagenicity of drinking water.