Uric acid is a metabolite obtained from purine by xanthine oxidase activity (XO) and high levels of serum uric acid leads to hyperuricemia and gout. Mesona procumbens Hemsl. has been used as a healthy beverage and a traditional remedy. In this study, the hypouricemic effects of M. procumbens extracts were evaluated in vitro and in vivo. The 50% ethanol extract of M. procumbens (EE50) showed the strongest inhibitory effect on monosodium urate (MSU)-induced XO activity in THP-1 cells. However, the phenolics and flavonoids in EE50 may not serve as inhibitors of XO. EE50 prevented an increase in the serum uric acid level in potassium oxonate (PO)-challenged ICR mice and streptozocin (STZ)-induced SD rats. EE50 down-regulated STZ-induced liver XO activity, and it restored renal OAT1 and urate transporter expression. STZ-induced renal interleukin-1β (IL-1β) and the tumor necrosis factor-α (TNF-α) level were inhibited by EE50 treatment. EE50 exhibits the hypouricemic effect via down-regulation of XO activity, suggesting that EE50 has potential to improve hyperuricemia and its complications.