This work reported the neuronal protection of low-dose lipopolysaccharide (LD-LPS) after spinal cord injury (SCI). SCI rat model was constructed, after adenovirus-mediated ALKBH5 vectors and shRNA transfection and LD-LPS pre-treatment. Hematoxylin and eosin, Nissl, TUNEL staining of spinal cord tissues were adopted to monitor pathological changes, neuronal survival and apoptosis. PC12 cells transfected with ALKBH5 vectors and ALKBH5/Nrf2 siRNAs were treated by LD-LPS, followed by oxygen and glucose deprivation/reoxygenation (OGD/R). Cell viability and apoptosis were assessed by cell counting kit-8 and TUNEL assays. Neuronal oxidative stress was evaluated by appraising MDA and SOD levels. ALKBH5 and Nrf2 expression was monitored through immunohistochemistry, Western blot and qRT-PCR. Methylated RNA immunoprecipitation assay and Dot-blot experiment were for Nrf2 m6A modification detection, while RNA pull-down assay was for the binding validation between ALKBH5 and Nrf2. In rats with SCI, LD-LPS relieved spinal cord tissue damage and neuronal apoptosis; enhanced neuronal survival; decreased MDA content; elevated SOD activity; down-regulated ALKBH5; up-regulated Nrf2; and facilitated Nrf2 m6A methylation. These above influences by LD-LPS were eliminated by ALKBH5. Similar results were found in the OGD/R-induced PC12 cells after LD-LPS treatment. ALKBH5 significantly blocked Nrf2 m6A methylation, and pulled down Nrf2 protein. In the OGD/R-induced PC12 cells, the repressed oxidative stress and apoptosis by ALKBH5 silencing was abrogated by Nrf2 knockdown. LD-LPS might alleviate neuronal apoptosis and oxidative stress after SCI by facilitating Nrf2 m6A methylation via reducing ALKBH5. It was proposed to be a novel strategy for SCI treatment.