Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), remain critical clinical challenges characterized by acute diffuse lung inflammation, alveolar-capillary barrier disruption, and refractory pulmonary edema, leading to high morbidity and mortality. The alveolar epithelium, a key structural and functional unit of the lung, plays a pivotal role in maintaining alveolar fluid homeostasis, which depends on coordinated transcellular ion transport and paracellular barrier integrity mediated primarily by the epithelial sodium channel (ENaC) and tight junction proteins. As a central regulator of alveolar fluid clearance, ENaC mediates sodium ion reabsorption across the alveolar epithelium, whereas tight junction proteins, including zonula occludens-1, occludin, and claudins, restrict paracellular leakage and maintain epithelial barrier integrity. In the pathological setting of ALI/ARDS, both ENaC and tight junction proteins undergo significant dysregulation, with reduced ENaC function leading to impaired alveolar fluid clearance and exacerbated edema, while alterations in the expression, distribution, and function of tight junction proteins further compromise barrier integrity. Despite their individual roles being increasingly recognized, the complex interplay between ENaC and tight junctions in the alveolar fluid homeostasis of ALI/ARDS, as well as the underlying regulatory mechanisms, remain incompletely understood. This review therefore focuses on the mechanistic and functional crosstalk between ENaC and tight junction proteins, integrating their coordinated roles in alveolar fluid transport, barrier dysfunction, and pulmonary edema, and discussing potential therapeutic strategies with this coupled regulatory system in ALI/ARDS.