Sepsis-associated acute kidney injury (SA-AKI) is a prevalent and life-threatening condition among critically ill patients. At present, studies on SA-AKI are still in the experimental stage, and comprehensively elucidating the pathogenesis of SA-AKI would effectively promote the development of diagnostic and therapeutic for SA-AKI. Emerging evidence highlights the critical role of cell-specific epigenetic dysregulation in the severity and progression of SA-AKI, particularly in monocytes, macrophages, neutrophils, endothelial cells (ECs), and renal tubular epithelial cells (RTECs). Classical epigenetic modifications, including DNA methylation and histone modifications, serve as pivotal regulators of gene transcription, influencing multiple pathological processes, including inflammatory responses, microcirculatory dysfunction, and metabolic reprogramming during SA-AKI. Therefore, this review aims to provide a comprehensive analysis of the underlying epigenetic mechanisms of SA-AKI progression and explore the potential of epigenetic markers as diagnostic tools and therapeutic targets. Finally, we propose that targeting epigenetic modifications could pave the way for novel diagnostic strategies and precision medicine to improve SA-AKI outcomes.