Abstract: Fraxinellone, the major component of Cortex Dictamni, is naturally degraded limonids compound. Fraxinellone has significant anti-inflammatory activity in acute liver injury model. However, the low solubility and permeability of fraxinellone limited its potential application and even therapeutic effects. The aim of the paper is to increase oral bioavailability of fraxinellone, thus improving its hepatoprotection effect In vivo. We evaluated the effects of different pH values and different solubilizer (PEG 6000, PVP K30, HP-β-CD, F68 and SDS) on the solubility of fraxinellone. The results showed that HP-β-CD increased solubility of fraxinellone up to 155 times compared to that of water. More than 2.1 mg·mL^-1 fraxinellone can be resolved when adding 20% HP-β-CD. Mouse acute liver injury model induced by CCl₄ was used to evaluate In vivo activity of fraxinellone with or without HP-β-CD. The result shows that the hepatoprotective activity of fraxinellone in 20% HP-β-CD solution has been significantly improved compared with that of fraxinellone solution without HP-β-CD: the former inhibited 59 percent the increase of enzyme activity of ALT in liver, while the latter only inhibited 20 percent. A LC-MS/MS method was also developed to determine the oral bioavailability of fraxinellone. Fraxinellone solution with or without HP-β-CD were administered intra-gastrically to rats, and it was found that the bioavailability of fraxinellone with HP-β-CD was 23%, while only 5% without HP-β-CD. The result showed that HP-β-CD can significantly increase the solubility and permeability of fraxinellone, and improve bioavailability 3.5 fold In vivo acute liver injury model as well as hepatoprotective effects with same dose by oral administration.