Abstract: Studies have shown that differentiated embryo-chondrocyte expressed gene 1 (DEC1) promotes osteoblast osteogenesis. To investigate the role of DEC1 in postmenopausal osteoporosis, we used the two genotypes of mice (Dec1^+/+ and Dec1^−/−) to establish an ovariectomy model and found that the bone loss was significantly lower in Dec1^−/− ovariectomy mice than in Dec1^+/+ ovariectomy mice. The expression levels of RUNX2 and OSX were significantly increased in Dec1^−/− ovariectomy mice, compared with Dec1^+/+ ovariectomy mice; however, the expression levels of NFATc1, c-Fos, CTSK, and RANKL/OPG ratio were significantly decreased in Dec1^−/− ovariectomy mice, compared with those in Dec1^+/+ ovariectomy mice. Likewise, DEC1 deficiency also suppressed the expression levels of IL-6 and IL-1β. Further results showed that the mRNA expression levels of Runx2, Osx, and Alp were significantly increased in bone marrow mesenchymal stem cells of Dec1^−/− ovariectomy mice, compared with those of Dec1^+/+ ovariectomy mice. Moreover, the mRNA levels of Il1b, Il6, Tnfa, and Ifng were significantly increased in bone marrow-derived macrophages (BMMs) of Dec1^+/+ovariectomy mice, compared with those of Dec1^+/+ sham mice, but not in Dec1^−/− ovariectomy BMMs, when compared with those in Dec1^−/− sham BMMs. Additionally, the expression levels of p-IκBα and p-P65 were significantly increased in Dec1^+/+ ovariectomy BMMs, compared with those in Dec1^+/+ sham BMMs, but did not increase in Dec1^−/− ovariectomy BMMs, compared with those in Dec1^−/− sham BMMs. Taken together, DEC1 deficiency inhibited the NF-κB pathway induced by ovariectomy, thereby decreasing cytokines and subsequently inhibiting the decrease of osteogenesis and the increase of osteoclastogenesis caused by ovariectomy. The findings may provide a novel understanding of postmenopausal osteoporosis development, and offer potential avenues for the disease intervention.