Sepsis is a serious disease resulting from an imbalanced host response to bacterial infection, in which macrophages play a crucial role. However, the connection between bacterial infection and macrophage phagocytosis remains largely unknown. Here, we provide evidence supporting the role of apurinic/apyrimidinic endonuclease 1 (APE1) in regulating bacterial infection and macrophage immune function during sepsis. We confirmed down-regulation of APE1 expression in macrophages from both in vitro and in vivo septic models. APE1 deficiency significantly increases the mortality rate of septic mice. Experiments using fluorescent latex beads and Escherichia coli uptake demonstrated that reduced APE1 levels inhibit macrophage phagocytosis. Specifically, APE1 deficiency activates GSK3β, leading to the ubiquitination and subsequent proteasomal degradation of NRF2, thereby reducing the expression of phagocytic receptors. Additionally, APE1 participates in the process through its redox function. In conclusion, APE1 is a critical protein involved in the evasion of macrophage phagocytosis by bacteria. Our study suggests that targeting the APE1/NRF2 axis could serve as a promising therapeutic strategy for sepsis and bacterial infections.