Mitochondria play a crucial role in energy production through oxidative phosphorylation (OXPHOS) and are involved in cell proliferation, metastasis, and deterioration. The electron transport chain (ETC) generates reactive oxygen species (ROS), which can cause oxidative stress and damage cellular components. Glutathione (GSH) is a key antioxidant that is primarily synthesized in the cytoplasm and transported to mitochondria as mitochondrial glutathione (mGSH). mGSH metabolizes hydrogen peroxide (H₂O₂) within mitochondria and maintains redox homeostasis. An imbalance in the ratio of mitochondrial ROS to mGSH can lead to cell dysfunction, apoptosis, necroptosis, and ferroptosis, contributing to various diseases. The study reviews the physiological functions, anabolism, and transport of GSH to mitochondria, as well as the relationships between mGSH levels, the GSH/GSSG ratio, programmed cell death, and ferroptosis. It also discusses diseases caused by mGSH deficiency and potential therapeutics. Key findings include the importance of maintaining the GSH/GSSG ratio and the role of mGSH in preventing oxidative damage and cell death. Therapeutic strategies such as increasing GSH levels, maintaining the GSH/GSSG ratio, and using mitochondrial-targeted antioxidants are explored to mitigate oxidative stress and its associated diseases.Mitochondria play a crucial role in energy production through oxidative phosphorylation (OXPHOS) and are involved in cell proliferation, metastasis, and deterioration. The electron transport chain (ETC) generates reactive oxygen species (ROS), which can cause oxidative stress and damage cellular components. Glutathione (GSH) is a key antioxidant that is primarily synthesized in the cytoplasm and transported to mitochondria as mitochondrial glutathione (mGSH). mGSH metabolizes hydrogen peroxide (H₂O₂) within mitochondria and maintains redox homeostasis. An imbalance in the ratio of mitochondrial ROS to mGSH can lead to cell dysfunction, apoptosis, necroptosis, and ferroptosis, contributing to various diseases. The study reviews the physiological functions, anabolism, and transport of GSH to mitochondria, as well as the relationships between mGSH levels, the GSH/GSSG ratio, programmed cell death, and ferroptosis. It also discusses diseases caused by mGSH deficiency and potential therapeutics. Key findings include the importance of maintaining the GSH/GSSG ratio and the role of mGSH in preventing oxidative damage and cell death. Therapeutic strategies such as increasing GSH levels, maintaining the GSH/GSSG ratio, and using mitochondrial-targeted antioxidants are explored to mitigate oxidative stress and its associated diseases.