Taxifolin loaded zein-caseinate nanoparticles (TZP) were fabricated by the anti-solvent method and were used as an oral delivery vehicle to improve their bioavailability in the rat. The formulations of TZP were optimized. With mass ratio of 1:1:2 between taxifolin, zein and sodium caseinate, the particle size and ζ potential of TZP were (168.74 ± 0.35) nm and ?(57.67 ± 0.25) mV, while the encapsulation and loading efficiency of taxifolin were (85.83 ± 0.89)% and (17.11 ± 0.88)%, respectively. After freeze-drying, TZP exhibited excellent redispersibility in water without aggregation. Physicochemical characterization showed that taxifolin existed in amorphous form in TZP and its interaction with the protein was observed. After encapsulating in TZP, the excellent dispersion of taxifolin in water significantly improve its diffusion velocity through a semi-permeable membrane. After oral administration, taxifolin and its 5 metabolites were identified in rat plasma by ultra high performance liquid chromatography (UPLC) with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). The dynamic variation of taxifolin and its metabolites in plasma were then quantified by UPLC with a triple-quadrupole typemass spectroscopy (UPLC-QqQ-MS/MS). A pharmacokinetic study showed that the bioavailability of taxifolin increased from 0.35% to 0.52% through TZP fabrication. The plasma concentration of taxifolin glucuronide and methylated taxifolin glucuronide was much higher than taxifolin. Glucuronidation was the dominating metabolism pathway of taxifolin in vivo.