Systemic inflammation induces cognitive impairment, yet the mechanism involved in this process is unclear. Neurotrophin receptor p75 (p75NTR) signaling is a key pathological factor contributing to neurobehavioral abnormalities in many neurodegenerative diseases. However, the role of p75NTR signaling in the regulation of sepsis-induced cognitive impairment remains largely to be elucidated. In this study, systemic inflammation was induced by cecal ligation and puncture (CLP). Neurobehavioral performances were evaluated by open field, novel object recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10), apoptosis marker cleaved caspase-3, ionized calcium binding adaptor molecule 1 (IBA1), proBDNF, p75NTR, c-Jun N-terminal kinase (JNK), and pJNK in the hippocampus were determined by enzyme-linked immunosorbent assay, western blot analysis, and immunofluorescence. The synaptic marker in the CA1 region of the hippocampus was assessed by Golgi staining. In the present study, we showed that systemic inflammation induced cognitive impairment, which was accompanied by increased expressions of hippocampcal proBDNF and p75NTR. Of note, we found that LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75NTR signaling modulator significantly reversed the sepsis-induced cognitive impairment and restored most of the abnormal biochemical parameters. Taken together, our study suggests that proBDNF/p75NTR signaling pathway might play a key role in the development of sepsis-induced cognitive impairment, whereas specific p75NTR inhibitor may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.