Background <p>Spinal cord injury (SCI) is a condition that causes significant disability in the central nervous system. The secondary injury phase, marked by inflammation, oxidative stress, and glial cell activation, is a major factor in neurological dysfunction. While the sonic hedgehog (Shh) signaling pathway is vital for neural development and repair, its precise role in the secondary injury process following SCI is not yet clear.</p> Objective <p>This study explores the regulatory function and potential mechanisms of the Shh signaling pathway in secondary SCI.</p> Methods <p>A T10 segment SCI model in rats was created using a modified Allen method. Interventions with an Shh pathway agonist (purmorphamine) and antagonist (cyclopamine) were applied. Neurological function recovery, histopathological changes, inflammatory cytokine expression, oxidative stress levels, and expression of Shh pathway-related molecules were evaluated through behavioral scoring (BBB and Reuter), HE staining, immunohistochemistry, ELISA, biochemical assays, RT-qPCR, and Western blot. Transcriptomic sequencing was also conducted to analyze differentially expressed genes and pathway enrichment features.</p> Results <p>The Shh signaling pathway was significantly activated by SCI, resulting in the upregulation of molecules such as Shh, Smo, and Gli1. Activation of the Shh pathway markedly improved neurological function scores, ameliorated spinal tissue structure, inhibited TNF-α and IL-1β expression, reduced MDA levels, increased SOD activity, and significantly attenuated microglial and astrocyte activation. In contrast, inhibition of the pathway exacerbated pathological damage and functional deficits.</p> Conclusion <p>The Shh signaling pathway exerts a neuroprotective effect during secondary SCI. Its activation effectively alleviates inflammation and oxidative stress, suppresses glial cell activation, and promotes neurological recovery.</p>