Sunflower, a key agricultural crop with a history of use in Chinese medicine, holds potential for hyperuricemia treatment. This study investigates the efficacy and mechanisms of flavonoids extracted from sunflower receptacles in managing hyperuricemia. Various ethanol extracts were tested in hyperuricemia rats to evaluate their effects on uric acid reduction, joint swelling alleviation, and liver and kidney damage. The 30% ethanol extract showed the most significant effects, reducing uric acid levels, alleviating joint swelling, and minimizing liver and kidney damage. Liquid chromatography-mass spectrometry analysis identified 16 active flavonoid compounds in this extract. Molecular docking and machine learning analysis identified quercetin as the strongest xanthine oxidase (XO) inhibitor, with apigenin 7-glucoside emerging as a novel candidate. Further computational studies, including Gaussian accelerated molecular dynamics simulations, energy landscape analysis, and Markov state models, revealed a similar XO inhibition mechanism to allopurinol for quercetin. Our findings underscore the therapeutic potential of sunflower receptacle flavonoids for hyperuricemia management. This research paves the way for incorporating sunflower-derived flavonoids into modern pharmacological approaches for hyperuricemia treatment.