Genistein (GEN), an isoflavonoid, offers multifunctional biological activities. However, its poor oral bioavailability, aqueous solubility, extensive metabolism, and short half-life restricted its clinical use. Therefore, the Phospholipon90H complex of genistein (GPLC) was prepared to enhance its biopharmaceutical properties and anti-inflammatory activity. GPLC was characterized by employing particle size and zeta potential, Fourier transforms infrared spectrophotometry, differential scanning calorimetry, powder x-ray diffractometry, proton nuclear magnetic resonance, aqueous solubility, dissolution, ex vivo permeation, oral bioavailability and in vivo anti-inflammatory activity. The complex showed high entrapment of GEN (∼97.88% w/w) within the Phospholipon90H matrix. Particle size and zeta potential studies confirmed the small particle size with the modest stability of GPLC. The characterization analysis supported the formation of GPLC through the participation of hydrogen bonding between GEN and Phospholipon90H. GPLC significantly enhanced the aqueous solubility (∼2-fold) compared to GEN. Dissolution studies revealed that GPLC drastically improved the GEN dissolution rate compared to GEN. Likewise, the complex improved the permeation rate across the membrane compared to GEN. GPLC formulation significantly enhanced the oral bioavailability of GEN via improving its Cmax, tmax, AUC, half-life and mean residence time within the blood circulation compared to GEN. The GPLC (∼20 mg/kg, p.o.) remarkably inhibited the increase in paw edema up to 5 h, compared to GEN and diclofenac. Results suggest that the Phospholipon90 complex is a superior and promising carrier for enhancing the biopharmaceutical parameters of GEN and other bioactive with similar properties.