Background <p>Spinal cord injury (SCI) is a devastating condition with limited therapeutic options. Tetramethylpyrazine (TMP) has shown therapeutic potential in mitigating SCI-related damage. This study investigates the role of TMP in regulating 5-methylcytosine (m⁵C) RNA modification and its impact on SCI recovery.</p> Methods <p>A rat model of SCI was induced via contusion injury, and TMP was administered intraperitoneally for 28&#xa0;days. Functional recovery was evaluated using the Basso-Beattie-Bresnahan (BBB) locomotor rating scale. Histopathological changes were assessed by hematoxylin–eosin (HE) staining, while inflammatory cytokines (IL-1β, IL-6, TNF-α) and oxidative stress markers (SOD, MDA) were quantified using enzyme-linked immunosorbent assay (ELISA) and colorimetric assays. In vitro, PC12 cells were exposed to lipopolysaccharide (LPS) to model SCI, and TMP's effects on apoptosis and inflammation were analyzed via flow cytometry and ELISA. Molecular docking, m⁵C RNA immunoprecipitation (RIP), reverse transcription quantitative PCR (RT-qPCR), and luciferase reporter assays were performed to elucidate the interaction between TMP, NSUN2, and XBP1.</p> Results <p>TMP treatment significantly improved motor function, reduced inflammation, and alleviated oxidative stress in SCI rats. In vitro, TMP dose-dependently reduced apoptosis and inflammatory cytokine levels in LPS-induced PC12 cells. TMP downregulated NSUN2 expression, leading to reduced m⁵C modification of XBP1 mRNA. Overexpression of NSUN2 increased XBP1 stability and expression, while knockdown of NSUN2 or overexpression of XBP1 modulated apoptosis and inflammation in PC12 cells.</p> Conclusions <p>TMP promotes functional recovery after SCI by modulating m⁵C RNA modification through the NSUN2-XBP1 regulatory axis. These findings suggest the therapeutic potential of TMP in SCI and provide novel mechanistic insights into the role of RNA modifications in neuroprotection and inflammation regulation.</p>