Acute respiratory distress syndrome (ARDS) is a severe clinical syndrome characterized by dysregulated inflammatory response caused by intrapulmonary and extrapulmonary injuries, and remains associated with high morbidity and mortality worldwide. Despite substantial advances in supportive care, the underlying pathogenesis of ARDS has not yet been fully elucidated. Emerging evidence suggests that epigenetic regulation plays a pivotal role in the development and progression of ARDS by modulating gene expression in response to environmental and inflammatory stimuli. Major epigenetic mechanisms include DNA methylation, histone modification and non-coding RNA-mediated regulation. As epigenetic alterations represent the interface between genetic susceptibility and environmental exposure, they may provide important insights into the heterogeneity and dynamic progression of ARDS. In this review, we summarize findings from in vitro studies, animal studies, and clinical studies to elucidate the role of epigenetic modifications in ARDS pathogenesis. Furthermore, we discuss the potential of epigenetic mechanisms as novel therapeutic targets and future directions for precision treatment strategies in ARDS.