OBJECTIVE: Our goal was to investigate the role of neutrophil extracellular traps (NETs) in the disruption of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and to evaluate the therapeutic efficacy of CD47-blocking antibodies in mitigating the disruption. METHODS: We utilized Evans blue extravasation to evaluate BSCB permeability and immunofluorescence to evaluate the formation of NETs and the expression of ZO-1, CD31, S100A8/A9, CD68, GFAP, Iba-1, and NeuN. Spinal cord edema was quantified by comparing the dry and wet weights of tissue samples. We used enzyme-linked immunosorbent assay (ELISA) to evaluate inflammatory factors, including IL-1β, IL-6, and TNF-α. Changes in genes associated with NET formation were identified by mRNA sequencing. Activation of the TLR4-NF-κB-MMP2/MMP9 signaling pathway was examined via Western blot analysis. Limb function was evaluated using the Basso Mouse Scale (BMS) to assess motor function. RESULTS: We observed massive aggregation of neutrophils and the formation of neutrophil extracellular traps (NETs) after spinal cord injury. The use of CD47-blocking antibodies reduced NET formation, mitigated S100A8/A9 production, attenuated BSCB injury, decreased inflammatory cell infiltration, alleviated spinal cord edema, and minimized neuronal death at the site of injury. Furthermore, these antibodies suppressed activation of the TLR4-NF-κB-MMP2/MMP9 signaling pathway. CONCLUSION: The use of CD47-blocking antibodies post-SCI resulted in reduced NET formation. By suppressing the TLR4-NF-κB-MMP2/MMP9 signaling pathway, these antibodies contributed to the preservation of blood-spinal cord barrier (BSCB) integrity, highlighting their potential as a therapeutic strategy for SCI.