Intracellular reactive oxygen species (ROS) accumulation is key to osteoclast differentiation. Plant-derived polyphenols that have reduced ROS production have been widely studied for the treatment of osteoporosis. However, these compounds are rarely absorbed in the small intestine and are instead converted to phenolic acids by the microbiota in the colon. These large quantities of low-molecular-weight phenolic acids can then be absorbed by the body. 4-Hydroxyphenylacetic acid (4-HPA) is an important metabolite of these polyphenols that is generated by the human intestinal microbiota. However, its potential mechanism is not fully understood. In this study, we aimed to elucidate the role of 4-HPA on osteoclastogenesis and treating osteoporosis. Our study showed that 4-HPA inhibited osteoclast differentiation and function and downregulated osteoclast-specific genes, including NFATc1, Atp6v0d2, MMP9, CTSK, Acp5, and c-Fos. As for further mechanism exploration, 4-HPA reduced ROS accumulation by regulating nuclear factor erythroid 2-related factor (Nrf2) and subsequently inhibited the nuclear factor kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) pathways. To evaluate the effect of 4-HPA on postmenopausal osteoporosis, an ovariectomized (OVX) mouse model was used. The Micro-CT and histomorphometry analyses showed that 4-HPA effectively prevents bone loss. Encouragingly, 4HPA demonstrated efficacy in treating osteoporosis induced by OVX. In conclusion, our study revealed that 4-HPA, a polyphenol metabolite produced by intestinal microorganisms, also inhibits osteoclast formation and treats osteoporosis, which provides a new experimental basis and candidate drug for the treatment of osteoporosis.