Hydrogen sulfide (H₂S) has been recognized as a toxic compound, but recent studies have shown that it is a crucial gaseous signaling molecule with significant physiological and pathological roles. H₂S mediates apoptosis through multiple signaling pathways, such as PI3K/Akt/mTOR and MAPK, in cancer cells. This review summarizes the role and mechanism of H₂S in cancer cell apoptosis in mammals. H₂S promotes cancer progression in various tissues through multiple mechanisms, including angiogenesis, increased mitochondrial bioenergy, and antioxidant effects. However, at higher concentrations, H₂S can inhibit these effects and induce apoptosis by suppressing bioenergetic and cytotoxic processes. The regulation of H₂S production and metabolism may improve cancer treatment effectiveness. The review also discusses the biphasic effects of H₂S on different cancers, the mechanisms of different H₂S concentrations, and the challenges in detecting H₂S concentrations in tissues and cells. Additionally, it explores the involvement of H₂S in three apoptotic pathways: intrinsic, extrinsic, and endoplasmic reticulum (ER) stress pathways, and its role in various cancers, including lung, esophageal, gastric, hepatocellular, pancreatic, colorectal, breast, urogenital, and hematologic cancers. The review highlights the potential of H₂S-releasing drugs and natural organic H₂S donors in cancer therapy and the need for more effective methods to detect H₂S levels in cancer cells.Hydrogen sulfide (H₂S) has been recognized as a toxic compound, but recent studies have shown that it is a crucial gaseous signaling molecule with significant physiological and pathological roles. H₂S mediates apoptosis through multiple signaling pathways, such as PI3K/Akt/mTOR and MAPK, in cancer cells. This review summarizes the role and mechanism of H₂S in cancer cell apoptosis in mammals. H₂S promotes cancer progression in various tissues through multiple mechanisms, including angiogenesis, increased mitochondrial bioenergy, and antioxidant effects. However, at higher concentrations, H₂S can inhibit these effects and induce apoptosis by suppressing bioenergetic and cytotoxic processes. The regulation of H₂S production and metabolism may improve cancer treatment effectiveness. The review also discusses the biphasic effects of H₂S on different cancers, the mechanisms of different H₂S concentrations, and the challenges in detecting H₂S concentrations in tissues and cells. Additionally, it explores the involvement of H₂S in three apoptotic pathways: intrinsic, extrinsic, and endoplasmic reticulum (ER) stress pathways, and its role in various cancers, including lung, esophageal, gastric, hepatocellular, pancreatic, colorectal, breast, urogenital, and hematologic cancers. The review highlights the potential of H₂S-releasing drugs and natural organic H₂S donors in cancer therapy and the need for more effective methods to detect H₂S levels in cancer cells.