Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern. Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their high safety and efficiency. (?)-Epigallocatechin-3-gallate (EGCG) is the most abundant and biologically active polyphenol in green tea. It can inhibit osteoclastogenesis in vitro by blocking receptor activator of nuclear factor (NF) -κB (RANK) signaling pathways. This study used the ovariectomized (OVX) mouse model to estimate the therapeutic effect of EGCG on osteoporosis and verified the molecular mechanism in vivo. The results revealed that EGCG significantly inhibited the OVX-induced body weight gain. Moreover, no adverse effects were observed on blood glucose, histomorphological features, weights, as well as indices of liver and kidney in OVX mice. EGCG could significantly ameliorate bone loss in OVX mice by inhibiting osteoclastogenesis. This effect was evidenced by the reduced number of osteoclasts and the increased trabecular bone area in the femurs. Moreover, EGCG inhibited the activities of c-telopeptide of type I collagen (CTX-I) and tartrate-resistant acid phosphatase 5b (TRACP-5b) and strengthened bone gla protein (BGP) and procollagen I N-terminal peptide (PINP) activities in OVX mice. Mechanistically, EGCG significantly downregulated the expression of osteoclastogenesis-related marker genes and proteins, including nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), c-Fos, tartrate-resistant acid phosphatase (TRAP), c-Src, and cathepsin K. In addition, the phosphorylation levels of p65, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and protein kinase B (AKT) were significantly suppressed in OVX mice. It was found that EGCG could alleviate OVX-induced bone loss in mice by suppressing osteoclastogenesis by blocking the NF-κB, mitogen-activated protein kinase (MAPK), and AKT signaling pathways. EGCG has the potential to prevent and treat osteoclast-related diseases such as osteoporosis.