Sepsis is a multiple organ dysfunction syndrome caused by a dysregulated host response to infection. The mortality rate remains high under current treatment methods, and there is an urgent need to explore new therapeutic targets. Ubiquitination modification, as a key posttranslational regulation mechanism of proteins, plays a central role in the occurrence and development of sepsis and multiple organ damage by regulating key pathological processes such as inflammatory response, cell death and barrier function. This article aims to systematically elucidate the molecular mechanism of ubiquitination modification system in sepsis related organ damage, summarize the latest research progress on treatment strategies targeting the ubiquitination pathway, and explore the challenges and future transformation directions faced in this field. Through comprehensive analysis of existing research, this review aims to provide new ideas and theoretical basis for precise treatment of sepsis.