Biomaterials carrying recombinant human bone morphogenetic protein 2 (BMP2) have been developed to enhance bone regeneration in the treatment of bone defects. However, various reports have shown that in the bone repair microenvironment, fibroblasts can inhibit BMP2-induced osteogenic differentiation in mesenchymal stem cells (MSCs). Thus, factors that can target fibroblasts and improve BMP2-mediated osteogenesis should be explored. In this project, we focused on whether or not an inhibitor of the NF-κB signaling pathway, QNZ (EVP4593), could play a synergistic role with BMP2 in osteogenesis by regulating the activity of fibroblasts. The roles of QNZ in regulating the proliferation and migration of fibroblasts were examined. In addition, the effect of QNZ combined with BMP2 on the osteogenic differentiation of MSCs was evaluated both in vitro and in vivo. Furthermore, the detailed mechanisms by which QNZ improved BMP2-mediated osteogenesis through the modulation of fibroblasts were analyzed and revealed. Interestingly, we found that QNZ inhibited the proliferation and migration of fibroblasts. Thus, QNZ could relieve the inhibitory effects of fibroblasts on the homing and osteogenic differentiation of mesenchymal stem cells. Furthermore, biomaterials carrying both QNZ and BMP2 showed better osteoinductivity than did those carrying BMP2 alone both in vitro and in vivo. It was found that the mechanism of QNZ involved reactivating YAP activity in mesenchymal stem cells, which was inhibited by fibroblasts. Taken together, our results suggest that QNZ may be a candidate factor for assisting BMP2 in inducing osteogenesis. The combined application of QNZ and BMP2 in biomaterials may be promising for the treatment of bone defects in the future.