Highly soluble cocrystals can be used to improve bioavailability of a poorly soluble drug, through generating supersaturation, when absorption is limited by drug dissolution. Dihydromyricetin (DMY) is a biopharmaceutics classification system (BCS) IV drug, exhibiting dissolution limited absorption. Two novel soluble cocrystals of (+/-)DMY with caffeine and urea were prepared, and their physicochemical properties were evaluated for suitability in formulation development. Although having a much higher solubility than ()DMY, both cocrystals undergo rapid precipitation during dissolution and form the poorly soluble ()DMY dihydrate in aqueous media. This negates the potential advantage offered by the high solubility of the two cocrystals in enhancing the dissolution rate and in vivo bioavailability. To solve this problem, we have systematically evaluated suitable crystallization inhibitors to maintain the supersaturation generated by cocrystal dissolution over a prolonged period of time. At 37 degrees C, an approximately 5-fold enhancement in oral bioavailability of (+/-)DMY was achieved when both cocrystals were dosed with 2.0 mg/mL polyvinylpyrrolidone K30 solution than (+/-)DMY dihydrate suspended in 0.5 mg/mL carboxymethylcellulose sodium solution. This study demonstrates that the use of a highly soluble cocrystal along with an appropriate crystallization inhibitor is a potentially effective formulation strategy for improving oral bioavailability of poorly soluble BCS IV drugs.