How to improve the neurogenic potential of mesenchymal stem cells (MSCs) and develop biological agent based on the underlying epigenetic mechanism remains a challenge. Here, we investigated the effect of histone demethylase Lysine (K)-specific demethylase 2B (KDM2B) on neurogenic differentiation and nerve injury repair by using MSCs from dental apical papilla (SCAP). We found that KDM2B promoted the neurogenic indicators expression and neural spheres formation in SCAP, and modified the Histone H3K4 trimethylation (H3K4me3) methylation on neurogenesis-related genes. KDM2B improved the SCAP mediated recovery of motor ability at the early healing stage of spinal cord injury rats. Meanwhile, KDM2B acted as a negative regulator to its partner EZH2 during neurogenic differentiation, enhancer of zeste homologue 2 (EZH2) suppressed the neurogenic ability of SCAP. Further, the protein interaction between KDM2B and EZH2 was identified which decreased during neurogenic differentiation. On this basis, we revealed seven key protein binding sequences of KDM2B to EZH2, and synthesized KDM2B-peptides based on these sequences. By the usage of KDM2B-peptides, EZH2 function was effectively intervened and the neurogenic ability of SCAP was promoted. More, KDM2B-peptides significantly improved the SCAP mediated functional recovery at SCI early phase. Our study revealed that KDM2B acted as a promotor to neurogenic differentiation ability of dental MSCs through binding and negatively regulating EZH2, and provided the KDM2B-peptides as candidate agents for improving the neurogenic ability of MSCs and nerve injury repair.