Acute Respiratory Distress Syndrome (ARDS) is a severe and life-threatening form of acute lung injury with high mortality. It affects approximately 150,000–190,000 patients annually in the United States, and a substantial proportion of patients require invasive mechanical ventilation for respiratory support. The progression of ARDS involves thrombo-inflammation, the disruption of the alveolar–capillary barrier, and oxidative injury within pulmonary tissues. Across diverse ARDS etiologies such as sepsis, aspiration, trauma, and COVID-19, the excessive production of reactive oxygen species (ROS) is a central mediator of lung injury. Central to the neutralization of oxidative stress is glutathione (GSH), a key intracellular antioxidant responsible for neutralizing ROS. Decreased levels of GSH have been associated with increased cytokine levels and thrombosis, but the full extent of GSH’s role in these processes remains unclear. This review provides an overview of the role of glutathione in the pathophysiological sequelae of ARDS, highlights its relevance in COVID-19-related lung injury, and explores its potential as a clinical marker to predict the need for mechanical ventilation.