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Abstract Background Despite the ongoing safety-driven spate of flavonoid xanthine oxidase (XOD) inhibition investigations, there is a lack of flavonoid-based uricostatic antihyperuricemic agents in clinical medicine. The poor pharmacokinetic profiles of glycosides (the natural form of existence of most flavonoids) relative to their aglycones could be largely responsible for this paradox. This investigation was aimed at providing both functional and molecular bases for the possible discovery of XOD inhibitory (or uricostatic) anti-hyperuricemic flavonoid aglycones from the leaves of a flavonoid-rich medicinal plant, Tribulus terrestris. To this end, the flavonoid aglycone fraction of T. terrestris leaf extract (FATT) was evaluated in vivo for antihyperuricemic activity in ethanol-induced hyperuricemic mice, monitoring serum and liver uric acid levels. Molecular docking and molecular dynamics simulation studies were carried out on the three major flavonoid aglycones of T. terrestris (isorhamnetin, quercetin and kaempferol) against an inhibitor conformation XOD model. The three flavonoids were also subjected to in vitro XOD activity assay, comparing their IC50 to that of allopurinol, a standard uricostatic antihyperuricemic drug. Results FATT significantly lowered serum uric acid (p