EZH2, a member of the polycomb repressive complex 2, induces trimethylation of the downstream gene at the histone three lysine 27 (H3K27me3) position to inhibit tumor cell proliferation. Here, we showed that the apoptosis rate and apoptotic protein expression increased after EZH2 inhibition, whereas key molecules of the NF-κB signaling pathway and the downstream target genes were inhibited. Additionally, the expression of CD155, a TIGIT high-affinity ligand in multiple myeloma (MM) cells, was decreased by the mTOR signaling pathway. Furthermore, the combination of EZH2 inhibitor and TIGIT monoclonal antibody blockade enhanced the anti-tumor effect of natural killer cells. In summary, the EZH2 inhibitor not only plays an anti-tumor role as an epigenetic drug, but also enhances the anti-tumor effect of the TIGIT monoclonal antibody by affecting the TIGIT-CD155 axis between NK cells and MM cells, thus providing new ideas and theoretical basis for the treatment of MM patients.