OBJECTIVES: Epigallocatechin gallate (EGCG) exhibits various biological effects, including antiviral, anti-inflammatory, cardioprotective, and lipid-regulating properties. This study aims to investigate the therapeutic effects and mechanisms of EGCG in spinal cord injury (SCI). MATERIALS AND METHODS: The bioinformatic databases were used to screen therapeutic target genes for drugs against SCI. Component-Target-Disease networks were constructed with Cytoscape software, and inter-target interactions were analyzed using the String database. Additionally, KEGG pathway enrichment analyses were conducted on the identified target genes. SCI was evaluated by detecting inflammation-related factors, H&E staining, and immunohistochemistry. Furthermore, ROS and JC1 staining were performed on HT22 cells subjected to various treatments. Molecular mechanisms were investigated using western blot and qRT-PCR analyses. RESULTS: Forty-four overlapping genes were identified as potential targets, with HMOX1, GPX-4, and HIF-1A emerging as central hub genes. Key pathways associated with these targets included Ferroptosis and HIF-1 signaling. In vivo studies demonstrated that EGCG effectively promotes motor function recovery and reduces the expression of proteins and genes such as IL-1β, IL-6, HIF-1α, and 4HNE. In vitro experiments showed that EGCG decreases ROS and intracellular lipid ROS levels in HT22 cells while increasing GPX-4 and HMOX1 expression to inhibit ferroptosis and HIF-1 signaling pathways. CONCLUSION: Our findings reveal a significant new mechanism by which EGCG can reduce SCI through the inhibition of ferroptosis, facilitated by the activation of HMOX1 expression and the down-regulation of the HIF-1 signaling pathway. This suggests its potential as a therapeutic option for this condition.