Enhancer of zeste homolog 2 (EZH2) has been noted to contribute to the pathogenesis of autoimmune diseases. This study sought to investigate the mechanism of EZH2 in osteoclast (OCL) and osteoblast (OBL) differentiation (OCLD/OBLD) and bone destruction in RA. The animal model of collagen-induced arthritis (CIA) was established, followed by arthritis index (AI) scoring and histological staining, and measurements of inflammatory cytokines levels. The number of OCLs was detected via Tartrate-resistant acid phosphatase (TRAP) staining, and levels of OBL markers were determined by Western blot analysis. Trimethylated histone H3 at lysine 27 (H3K27me3) expression and its enrichment in the Ndrg2 promoter were detected. Collaborative experiments were performed with GSK-J1 or sh-Ndrg2 in CIA mice with EZH2 knockdown. EZH2 was upregulated while Ndrg2 was downregulated in knee joint tissues of CIA mice. Silencing EZH2 reduced AI scores, pathological injury of the knee joint, levels of inflammatory cytokines, and TRAP-positive cells, and increased protein levels of RUNX2 and BMP2. EZH2 promoted H3K27me3 level in the Ndrg2 promoter to inhibit Ndrg2 transcription. H3K27me3 upregulation or Ndrg2 downregulation reversed the role of silencing EZH2 in bone destruction. Overall, EZH2 repressed OBLD and promoted OCLD to aggravate bone destruction in CIA mice through H3K27me3/Ndrg2.