Epigenetic modification includes DNA methylation, histone modification, non-coding RNA, etc., and is crucial in determining gene expression. A growing number of recent studies have shown that epigenetic regulation may play a central role in the pathogenesis of sepsis. Due to its explicit mechanism and relatively mature technic, DNA methylation has received extensive attention in sepsis-related researches. By examining recent studies on septic DNA methylation mechanism, this review elucidates the key role in sepsis occurrence and progression that DNA methylation plays from etiology, immunology and other aspects, as well as its application potential in the diagnosis, prognosis and treatment of sepsis before pointing out the direction for further research.