Objective To investigate the effects of xanthohumol (XAN) on reducing serum uric acid (UA) and regulating bone metabolism in hyperuricemia (HUA) rats. Methods Totally 48 male Wistar rats were randomly divided into 6 groups (n=8):blank group, model group, allopurinol (ALLO) group, XAN low-dose (XAN-L) group, XAN medium-dose (XAN-M) group, and XAN high-dose (XAN-H) group. The HUA model was developed by the combined use of potassium oxonate (200 mg·kg^-1·d^-1) and hypoxanthine (250 mg·kg^-1·d^-1). After HUA model was established for 2 h, corresponding concentrations of drug suspension (20 mg·kg^-1·d^-1 in ALLO group, 5 mg·kg^-1·d^-1 in XAN-L group, 15 mg·kg^-1·d^-1 in XAN-M group, and 45 mg·kg^-1·d^-1 in XAN-H group) was administered to gavage for 14 d. Orbital blood was collected on the 3^rd, 7^th, 10^th and 14^th d to detect the levels of serum UA, creatinine (CRE), blood urea nitrogen (BUN), and activity of xanthinoxidase (XOD) in each group. At the end of the experiment, the activity of alkaline phosphatase (ALP), the levels of bone metabolism-related proteins such as Runt-related transcription factor 2 (Runx 2), cathepsin K (CTSK), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) were measured, and then the ratio of RANKL/OPG was analyzed. Results Compared with the blank group, the serum levels of UA in rats of model group were significantly increased on the 3^rd, 7^th, 10^th and 14^th d (all P<0.01), indicating that the HUA model was successfully constructed. Compared with the model group, both XAN-M and XAN-H effectively reduced the levels of serum UA in acute and chronic HUA rats (all P<0.01), inhibited the XOD activity (all P<0.01), and improved the renal function indexes CRE (all P<0.01) and BUN (all P<0.05). Although XAN-L did not significantly reduce the serum UA level in acute HUA rats, it effectively decreased the XOD activity (P<0.01) and improved its renal function indexes CRE (P<0.01) and BUN (P<0.05); while for chronic HUA rats, it had descending effects on the serum UA level (all P<0.01), but had no obvious renal protective effect. In addition, XAN also significantly enhanced ALP activity (all P<0.01), up-regulated the expression of Runx2 (all P<0.01, except for XAN-L group), down-regulated the expression of CTSK (all P<0.01), inhibited the secretion of RANKL (all P<0.01), promoted the expression of OPG (P<0.01, only for XAN-H group), and corrected the ratio of RANKL/OPG (all P<0.05). Conclusion XAN has active descending effects on serum levels of UA in HUA rats, which may be related to inhibiting XOD activity to reduce UA production and protecting renal function to enhance UA excretion. Meanwhile, XAN can also promote bone formation, inhibit bone destruction, and effectively regulate bone metabolism, which may be related to the inhibition of osteoclast differentiation through RANKL/OPG signaling pathway.