Abstract: Sepsis has high incidence and lack of effective treatment, and it is the leading cause of death in intensive care unit. The endoplasmic reticulum is an organelle, and it is responsible for a series of physiological activities such as protein folding and assembly. Under certain conditions, the endoplasmic reticulum can lose homeostasis, leading to the accumulation of unfolded or misfolded proteins, which is known as endoplasmic reticulum stress (ERs). ERs is associated with sepsis and its related organ dysfunction. This review reviewed the recent advances in ERs, unfolded protein response (UPR) signaling pathways related to sepsis. At the same time, the potential significance of ERs as a therapeutic target for sepsis and its future development direction were discussed.