Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for efficient and cost-effective treatments to decrease the risk of CVD. The sigma-1 receptor (S1R) plays a role in the development of cardiac hypertrophy, heart failure, ventricular remodeling, and various other cardiac diseases. Preclinical studies have shown that S1R activation has considerable beneficial effects on the cardiovascular system, and this knowledge might contribute to informing clinical trials associated with the prevention and treatment of CVDs. Therefore, the objective of this review was to investigate the mechanisms of S1R in CVD and how modulation of pathways contributes to cardiovascular protection to facilitate the development of new therapeutic agents targeting the cardiovascular system.