Sepsis is characterized by organ dysfunction resulting from a dysregulated inflammatory response triggered by infection, involving multifactorial and intricate molecular mechanisms. Hypoxia-inducible factor-1α (HIF-1α), a notable transcription factor, assumes a pivotal role in the onset and progression of sepsis. This review aims to furnish a comprehensive overview of HIF-1α's mechanism of action in sepsis, scrutinizing its involvement in inflammatory regulation, hypoxia adaptation, immune response, and organ dysfunction. The review encompasses an analysis of the structural features, regulatory activation, and downstream signaling pathways of HIF-1α, alongside its mechanism of action in the pathophysiological processes of sepsis. Furthermore, it will delve into the roles of HIF-1α in modulating the inflammatory response, including its association with inflammatory mediators, immune cell activation, and vasodilation. Additionally, attention will be directed toward the regulatory function of HIF-1α in hypoxic environments and its linkage with intracellular signaling, oxidative stress, and mitochondrial damage. Finally, the potential therapeutic value of HIF-1α as a targeted therapy and its significance in the clinical management of sepsis will be discussed, aiming to serve as a significant reference for an in-depth understanding of sepsis pathogenesis and potential therapeutic targets, as well as to establish a theoretical foundation for clinical applications.© 2024. The Author(s).