Spinal cord injury (SCI) is one of the most devastating central lesions, and mitochondrial function plays an important role in secondary injury after SCI. Polydatin (PD) is a natural glycosylated precursor of resveratrol, showing mitochondrial preservation effects in the central nervous system. This study aimed to identify the hub target genes of PD on mitochondrial membrane potential (MMP) in SCI. A comprehensive analysis was performed on SCI-related genes, MMP-related genes, and PD targets screening from public databases. Differential expression analysis was conducted to identify differentially expressed genes (DEGs) in SCI. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were employed to assess pathway enrichment. Protein-protein interaction (PPI) network analysis and molecular docking were conducted to identify key genes and evaluate the binding affinity between PD and hub genes. A total of 16,958 SCI-related genes, 2,786 MMP-related genes, 318 PD-related target genes, and 7229 DEGs were identified. Intersection analysis revealed 46 genes common to all four categories. GSEA and GSVA analysis identified significant enrichment of pathways associated with suppressed and activated SCI biological processes. The PPI network analysis identified seven core hub genes: <i>EGFR, SRC, VEGFA, STAT3, ERBB2, TP53,</i> and <i>RHOA.</i> Molecular docking revealed strong binding affinities between PD and <i>ERBB2, EGFR</i>, and <i>RHOA</i>. The findings based on computational investigation from public databases suggest that PD may have therapeutic potential for SCI by modulating MMP. These results contribute to the understanding of SCI pathogenesis and the development of novel therapeutic strategies.