<p>Sepsis, a life-threatening condition characterized by organ dysfunction due to dysregulated host response to infection, remains a global health challenge with high morbidity, mortality, and long-term sequelae. The development of sepsis-associated organ dysfunction (SAODs) substantially worsens prognosis. Despite extensive studies, the pathophysiological mechanisms underlying sepsis and SAODs remain unclear. Protein acetylation is a widespread and reversible post-translational modification regulated by acetyltransferases and deacetylases that occurs on both histone and non-histone proteins. This modification plays a critical role in modulating various cellular processes by modifying target proteins. Emerging evidence indicates that acetylation is involved in sepsis and SAODs through regulation of key biological processes. In this review, we discuss the regulatory enzymes and mechanisms of acetylation, highlight their roles in sepsis and associated organ dysfunction, and explore the potential of acetylation modulators as therapeutic agents, offering new insights into understanding sepsis and developing novel therapeutic strategies.</p>