Objective ·To analyze the correlation between platelet activation indices and xanthine oxidase (XO) activity in patients and the underlying molecular mechanisms. Methods ·Between January 2023 and June 2025, 24 patients with hyperuricemia were recruited from the Department of Rheumatology and the Physical Examination Center of Huashan Hospital, Fudan University. Twenty-four healthy volunteers from the same center during the same period served as the healthy control group. Demographic data (age, gender), comorbidities, and medication history of all subjects were collected, and their fasting venous blood was drawn. Washed platelets were prepared for subsequent assays. The expression levels of P-selectin and platelet activation complex-1 (PAC-1) on the platelet surface were determined by flow cytometry, while platelet XO activity was measured via an absorbance assay. Spearman correlation analysis was performed to evaluate the relationships between uric acid levels, XO activity, and platelet activation markers. The effects of various concentrations of febuxostat on platelet aggregation induced by collagen, adenosine diphosphate (ADP), U46619, and thrombin were assessed. Platelet spreading on fibrinogen was analyzed. Furthermore, thrombin-induced intraplatelet reactive oxygen species (ROS) production was measured. Results ·Compared with the healthy control group, patients in the hyperuricemia group exhibited significantly higher platelet surface expression of P-selectin and PAC-1 (both P<0.05). However, neither marker showed a significant correlation with serum uric acid levels (both P>0.05). Platelet XO activity showed a positive correlation with thrombin-induced P-selectin expression (r=0.453, P=0.001) and PAC-1 expression (r=0.478, P=0.001). Febuxostat at concentrations of 50 μmol/L and 100 μmol/L significantly inhibited collagen, ADP, U46619, and thrombin-induced platelet aggregation and also significantly suppressed the spreading of platelets on fibrinogen. These inhibitory effects were statistically significant (all P<0.05) and intensified with increasing concentrations of febuxostat, demonstrating a concentration-dependent manner. Meanwhile, febuxostat treatment significantly reduced intraplatelet ROS generation in response to thrombin stimulation (P<0.05). Conclusion ·Platelet activation markers are higher in hyperuricemia patients than in the healthy control group. The expression levels of P-selectin and PAC-1 on the platelet surface show a positive correlation with intraplatelet XO activity. XO inhibitors can modulate platelet activation by reducing intracellular ROS production.