Background: Interest in water chemical activity, its content, and its impact on human health has greatly increased throughout the last decade. Some studies suggest that drinking water with high hardness may have preventative effects on cardiovascular diseases. This study aims to investigate the association between drinking water hardness and cardiovascular disease (CVD) mortality. Methods: The study selection process was designed to find the association between drinking water hardness and CVDs mortality. The search included both qualitative and quantitative research and was performed in three databases: Web of Science (Clarivate Analytics, Ann Arbor, MI, USA), PubMed (National Institute of Health, Bethesda, MA, USA), and Scopus (Elsevier, RELX Group plc, London, UK). The project was registered in the International Prospective Register of Systematic Reviews (PROSPERO), registration number: CRD42020213102. Results: Seventeen studies out of a total of twenty-five studies qualitatively analyzed indicated a significant relation between total water hardness and protection from CVD mortality. The quantitative analysis concluded that high drinking water hardness has a significantly lowering effect on mortality from CVDs, however, the heterogeneity was high. Conclusions: This systematic literature review shows that total water hardness could affect CVD prevention and mortality. Due to the many confounding factors in the studies, more research is needed.