Cardiovascular disease (CVD) is the leading cause of mortality and morbidity, accounting for major public health concerns worldwide. CVD poses an immense burden on the global healthcare system and economy. Ischemic heart disease, stroke, heart failure, atherosclerosis, and hypertension are the major diseases belonging to CVDs and ischemic heart diseases and stroke contribute to most CVD-induced deaths. Previously published review articles focused on the role of SIRT6 in CVDs but did not focus on the important role of SIRT6 in modulating the signaling pathways involved in CVDs and targeting them to treat CVDs. Thus, this review aims to identify and delineate the major signaling pathways that are involved in CVDs and whether SIRT6 can modulate those pathways to improve and treat CVDs. Alongside possible applications of small molecule modulators of SIRT6 in cardiovascular disease treatment have been comprehensively analyzed.