Excessive osteoclast (OC) activity together with relatively weak osteoblast (OB) function are strongly connected to osteolytic diseases, including osteoporosis, tumor‐induced osteolysis, and inflammatory bone erosion. Very few natural products or compounds have been shown to exert therapeutic effects on both OCs and OBs, limiting the potential development of natural compounds for clinical application. Hymenialdisine (HMD) is a marine sponge–derived natural inhibitor of protein kinases with previously reported anti‐osteoarthritis and anti‐cancer properties. However, the roles of HMD in OCs, OBs, and osteoporosis have not yet been well established. Here, we found that HMD not only suppressed osteoclastogenesis but also promoted OB differentiation. HMD exerted dose‐dependent inhibitory effects on RANKL‐induced OC formation, bone resorption, and OC‐specific gene expression. These strong inhibitory effects were achieved by blocking the NF‐κB and MAPK signaling pathways, and NFATc1 expression. In addition, HMD potentially stimulated OB differentiation by activating alkaline phosphatase (ALP) and enhancing OB matrix mineralization. We found that HMD can activate the glycogen synthase kinase 3β (GSK‐3β)/β‐catenin/T‐cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway to upregulate Runx‐2 expression, the main transcription factor in this pathway. Increased expression of Runx‐2 was also correlated with expression of the OB‐specific genes Col1a1 and osteocalcin (Ocn). Furthermore, we also evaluated the therapeutic potential of HMD in a female C57BL/6j mouse model of ovariectomy (OVX)‐induced systematic bone loss. HMD showed a remarkable ability to prevent decreases in bone volume (BV/TV) and trabecular thickness (Tb.Th). In summary, HMD exerts notable effects in inhibiting OC‐related osteolysis and enhancing OB‐induced ossification, suggesting the potential application of HMD in osteoporosis treatment.