Sepsis is a life-threatening condition marked by an abnormal host response to infection that can result in organ dysfunction, making it recognized as one of the primary causes of acute respiratory distress syndrome (ARDS). The pathophysiology of sepsis involves a cascade of events, including heightened pulmonary capillary permeability, dysfunction of alveolar epithelial cells, and the infiltration of inflammatory cells, such as neutrophils, macrophages, monocytes, and lymphocytes. The presence of these inflammatory cells triggers capillary leakages, alveolar epithelial damage, and the accumulation of fluid within the alveolar spaces, leading to compromised gas exchange, acute respiratory failure, and the progression to ARDS. In this complex scenario, Hypoxia-Inducible Factor-1α (HIF-1α) emerges as a pivotal player in maintaining cellular oxygen homeostasis and responding to hypoxia and inflammatory stimuli. This narrative review delves into the intricate molecular and biological characteristics of HIF-1α, elucidating its regulatory role within the context of sepsis and ARDS. By exploring the therapeutic potential of targeting HIF-1α, this review seeks to offer valuable insights into the underlying mechanisms linking sepsis to ARDS. Ultimately, this exploration of HIF-1α seeks to enhance our comprehension of sepsis pathogenesis, identify novel therapeutic avenues, and lay a strong theoretical groundwork for future clinical interventions.