Mulberry has favorable antioxidant ability. Menopause is a major cause of osteoporosis in women, and it is partially associated with oxidative stress. Here, mulberry water extract (MWE) was fed to ovariectomic (OVX) rats to explore the potential effect of MWE on osteoporosis. The results revealed that plasma alkaline phosphatase (ALP) significantly decreased in the OVX rats after MWE administration for 8 weeks. Histological examination showed that the MWE increased the density of trabecular bone in the OVX rats. It also revealed that the MWE increases the expression of Runx2 and decreases that of the receptor activator of nuclear factor κB and its ligand in the OVX rats. This implies that MWE might regulate osteoblast differentiation and osteoclast proliferation. The MWE improved the antioxidant status by lowering the expression of heme oxygenase-1. In addition, the MWE increased the expression of osteocalcin, ALP, and bone morphogenetic protein-2 in an osteoblast cell line, MG-63. The present results imply that MWE has potential to decelerate osteoporosis in an experimental OVX rat model.