The natural product aesculin was demonstrated to possess potent hypouricemic effects in in vivo models of hyperuricemia in both mice and rats pretreated with oxonate. Aesculin, when administered intraperitoneally to the oxonate-induced hyperuricemic rodents, was able to elicit dose-dependent hypouricemic effects. At doses of 150 mg/kg of aesculin or above, the serum urate levels of the oxonate-pretreated mice were not different from normal mice. Such an effect in mice was observed as quick as 1.5 h after aesculin administration and was persistent for at least 5 h after aesculin administration. In rats, similar hypouricemic effects of intraperitoneally administered aesculin could also be demonstrated at doses of 100 mg/kg of aesculin or above, the serum urate levels of the oxonate-pretreated rats were not different from normal rats. Again, the effect persisted for at least 5 h after aesculin administration. In both rodents, however, oral administration at the same doses did not produce any observable hypouricemic effects. In addition, aesculin, when tested in vitro on rat and mouse liver homogenates, did not elicit any measurable inhibitory actions on the xanthine oxidase/xanthine dehydrogenase activities.