Purpose <p>Chrysin has many pharmacological activities but suffers from low bioavailability (BA) due to its poor solubility and intestinal first-pass effect. This study aimed to develop a chrysin formulation that enhances its BA by inhibiting intestinal metabolism and increasing solubility.</p> Methods <p>A solid dispersion of chrysin (chrysin-SD) was prepared using the spray-drying method and characterized for solubility, metabolic inhibition, and pharmacokinetic properties of chrysin-SD in rats.</p> Results <p>Sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone (PVP) were selected as solubility-enhancing surfactants as well as inhibitors of chrysin glucuronidation and hydrophilic carriers, respectively. The optimized formulation had a chrysin: SDS: PVP ratio of 1:5:3 (w/w/w). Chrysin-SD increased chrysin solubility by 848-fold and the dissolution rate to 72.3% of the initial amount, compared to 3.11% for pure chrysin. This improvement was attributed to SDS, PVP, and the amorphous nature of chrysin-SD. Additionally, chrysin-SD increased absorptive permeability in the duodenum, jejunum, and ileum by 2.99- to 7.33-fold in rat models, without affecting secretory permeability. Chrysin-SD also suppressed the formation of chrysin glucuronide (chrysin-G), suggesting enhanced intestinal absorption through increased intestinal permeability and decreased intestinal glucuronidation. These findings were confirmed by a 19.7-fold increase in chrysin’s area under the curve (AUC) and a 93% reduction in the chrysin-G metabolic ratio compared to the pure chrysin group.</p> Conclusion <p>The chrysin-SD formulation with a chrysin: SDS: PVP ratio of 1:5:3 (w/w/w) significantly enhanced chrysin’s BA. This strategy, which improves solubility, dissolution, and intestinal absorption while reducing metabolism, offers a promising approach for enhancing the oral BA of herbal medicines like chrysin.</p>