Simple Summary Cancer mortalities are growing at an alarming pace around the globe, a fact related to challenges, such as side effects, selectivity, and resistance, accompanied by cancer therapy. Continuous development of preventive and therapeutic agents is urgently needed. Drug repurposing is a favored drug discovery strategy resulting in faster, safer, easier, and cheaper repurposed drugs. This review shows the clinical benefits of chronically used anti-diabetic and anti-hypertensive drugs in preventing and treating different human malignancies through a repurposing strategy. The safety, tolerability, effectiveness at low doses, and suitability for long-term use of chronically used medications offer exceptional benefits over other drug classes. Promising clinical evidence exists for anti-diabetic and anti-hypertensive agents for treating different human malignancies. As some have reached Phase IV evaluations, this review offers new insights for clinicians in managing cancer, diabetes, and hypertension. Despite the advancement in drug discovery for cancer therapy, drug repurposing remains an exceptional opportunistic strategy. This approach offers many advantages (faster, safer, and cheaper drugs) typically needed to overcome increased challenges, i.e., side effects, resistance, and costs associated with cancer therapy. However, not all drug classes suit a patient's condition or long-time use. For that, repurposing chronically used medications is more appealing. This review highlights the importance of repurposing anti-diabetic and anti-hypertensive drugs in the global fight against human malignancies. Extensive searches of all available evidence (up to 30 March 2023) on the anti-cancer activities of anti-diabetic and anti-hypertensive agents are obtained from multiple resources (PubMed, Google Scholar, ClinicalTrials.gov, Drug Bank database, ReDo database, and the National Institutes of Health). Interestingly, more than 92 clinical trials are evaluating the anti-cancer activity of 14 anti-diabetic and anti-hypertensive drugs against more than 15 cancer types. Moreover, some of these agents have reached Phase IV evaluations, suggesting promising official release as anti-cancer medications. This comprehensive review provides current updates on different anti-diabetic and anti-hypertensive classes possessing anti-cancer activities with the available evidence about their mechanism(s) and stage of development and evaluation. Hence, it serves researchers and clinicians interested in anti-cancer drug discovery and cancer management.