Sepsis is an organ dysfunction caused by a dysregulated host response to infection, often characterized by immune dysfunction. This condition typically manifests as an excessive inflammatory response at early stages, followed by immunosuppression at later stages. Due to this immunosuppressive state, patients with sepsis are susceptible to new infections, termed secondary infections, even after the primary infection has been controlled or resolved. In recent years, secondary infections in sepsis have garnered increasing clinical attention due to their risks to exacerbate the disease course, prolong hospital stay, and increase mortality risk. The sepsis-induced immunosuppression is central to the development of secondary infections, especially at the later stage of sepsis. Specifically, T cell function becomes impaired, natural killer cell activity decreases, and macrophage phagocytic ability weakens, all contributing to diminished immune surveillance. Additionally, the immune evasion mechanisms employed by pathogens responsible for secondary infections further complicate treatment. This review aims to elucidate the mechanisms of immunosuppression and its clinical significance in sepsis-related secondary infections, providing a guidance for optimizing treatment strategies.