Homocysteine (HCY) is a risk factor for atherosclerosis-related cardiovascular diseases. HCY increases oxidative stress, activates MMP, and alters calcium homeostasis, thereby leading to vascular dysfunction. The major source of oxidative stress in HCY-induced vascular remodeling is the mitochondria. HCY causes activation and the mitochondrial translocation of calpain-1 (calcium-dependent cysteine protease), thereby increasing intramitochondrial oxidative stress leading to the induction of MMP-9. Ample studies have focused on the role of HCY in vascular dysfunction. HCY increases fibrosis and causes cardiac contraction dysfunction; however, the role of HCY on the cardiomyocytes is not understood. HCY increases the expression of mitochondrial MMP-9, and induces mitochondrial permeability transition, leading to a decline in cardiomyocyte contractile function by agonizing the NMDA receptor. In the present review, the role of hydrogen sulfide in HCY-induced myocardium protection is summarized. Furthermore, the role of HCY-induced oxidative stress in the mitochondria in the regulation of myocyte contractility is discussed.