Ischemia–reperfusion injury, a critical pathophysiological phenomenon in multiple organ systems, remains a formidable therapeutic challenge in clinical practice. As the third endogenously produced gaseous signaling molecule, hydrogen sulfide (H
2
S) has emerged as a pivotal regulator of diverse physiological processes and pathological cascades. Accumulating evidence indicates that H
2
S exerts cytoprotective effects against cerebral, cardiac, hepatic, renal, and pulmonary ischemia–reperfusion injuries through multifaceted mechanisms involving mitigation of inflammatory responses, suppression of oxidative stress, modulation of autophagic processes, and inhibition of apoptotic pathways. This comprehensive review systematically examines the endogenous biosynthesis and metabolic regulation of H
2
S, while elucidating the molecular mechanisms underlying its organ protective effects during ischemia–reperfusion injury. Particular emphasis is placed on the therapeutic potential of H
2
S synthase isoforms and bioactive metabolites in ischemic pathophysiology. Notably, recent advances in H
2
S pharmacology have catalyzed the development of novel H
2
S donors and slow-releasing compounds, including HSDF-NH
2
, S-allyl cysteine, S-propargyl cysteine, and S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-L-cysteine. These pharmacological innovations demonstrate enhanced tissue specificity and controlled release kinetics, paving the way for clinical translation of H
2
S-based therapeutics in ischemia–reperfusion injury management. Future research directions should focus on optimizing drug delivery systems and elucidating the spatiotemporal dynamics of H
2
S signaling in organ-specific ischemia–reperfusion pathologies.