BACKGROUND: Spinal cord injury (SCI) remains a devastating central nervous system disorder. The complex pathological microenvironment following SCI, particularly the imbalance in neuroinflammation, contributes to its therapeutic challenges. Microglial pyroptosis, a type of programmed cell death, is pivotal in exacerbating neuroinflammation and secondary tissue damage after SCI. Our previous study demonstrated the inhibitory efficacy of conditioned medium (CM) derived from human dental pulp stem cells (DPSCs) on the microglial pyroptosis and its positive effects on the functional recovery in SCI models. However, the major secretory product in CM responsible for inhibiting microglial pyroptosis remains unclear. OBJECTIVE: We aim to investigate whether vascular endothelial growth factor (VEGF) secreted by human DPSCs can alleviate microglial pyroptosis through the PI3K/AKT signaling pathway and promote motor and electrophysiological function recovery in SCI mice. METHODS: Human DPSCs were isolated and cultured, and CM was collected for VEGF detection and further treatment. The BV2 cell line was established as a microglial pyroptosis model through the administration of lipopolysaccharide (LPS). SCI was induced in mice. Molecular and histological techniques were employed to evaluate pyroptosis and explore the underlying mechanisms both in vivo and vitro. RESULTS: Human DPSC-derived VEGF significantly inhibited microglial pyroptosis both in vitro and vivo, as evidenced by the decreased expression of pyroptosis-related markers, such as caspase-1 and IL-1β. The anti-pyroptotic effects of VEGF were closely associated with the activation of the PI3K/AKT signaling pathway, which was identified as a key regulatory mechanism. Importantly, treatment with DPSC-CM improved the recovery of motor function and electrophysiological conduction in SCI mice. CONCLUSION: Human DPSC-derived VEGF alleviates microglial pyroptosis via the PI3K/AKT signaling pathway, thereby contributing to the repair of SCI. Our study provides new insights into the potential for therapy of DPSCs and their secreted factors, particularly VEGF, offering new perspectives on the treatment of SCI.