Hydrogen sulfide (H₂S), once considered merely a toxic gas, is now recognized as a key endogenous signaling molecule with profound effects on vascular tone, inflammation, and cytoprotection. Central to its physiological roles is a tightly regulated balance between synthesis and degradation. While much attention has been given to H₂S biosynthesis and its signaling functions, its catabolism – particularly through the mitochondrial sulfide oxidizing pathway – has received comparatively less pharmacological exploration. This pathway not only serves as a critical detoxification mechanism but also links H₂S oxidation directly to cellular bioenergetics by contributing to mitochondrial ATP production. Such coupling underscores a unique intersection between gasotransmitter regulation and energy metabolism. This chapter highlights the bioenergetic significance of H₂S degradation, emphasizing how modulation of its mitochondrial catabolic machinery could serve as a novel therapeutic strategy. By modulating H₂S clearance, especially in pathologies marked by disrupted sulfur homeostasis and mitochondrial dysfunction, targeted pharmacological intervention may restore metabolic balance and cellular energy efficiency.