Application of local anesthetic reagents, such as lidocaine (Lid), could cause significant neurotoxicity in spinal cord dorsal root ganglia neurons (DRGNs). In this study, we investigated the potential rescuing effect of cordycepin (CDC) in an in vitro explant model of lidocaine-induced apoptosis in DRGNs. Explant of rat neonatal DRGNs was prepared, and treated with Lid in vitro to induce neuronal apoptosis. Prior to Lid treatment, DRGN explant was pre-incubated with various concentrations of CDC to evaluate its rescuing effect on Lid-induced apoptosis. We found that, in cultured DRGNs, Lid caused significant neuronal apoptosis whereas pre-incubation of CDC rescued Lid-induced neurotoxicity. In addition, gene and protein expressions of Caspase-9 and Matrix metalloproteinase 3 (MMP3), a key component of inflammatory signal pathway, were both upregulated by Lid but downregulated by CDC pre-incubation. We further overexpressed MMP3 in cultured DRGNs. And discovered that forced MMP3 overexpression upregulated endogenous MMP3 and caspase-9, and reversed the rescuing effect of CDC on Lid-induced neurotoxicity in DRGNs. Therefore, we concluded that CDC has protective effect on local anesthesia induced spinal cord neurotoxicity, possibly through the inverse regulation on inflammatory signaling pathway.