Daidzein (Dai) exhibits a variety of pharmacologic actions. However, the low solubility and high crystallinity limit the bioavailability of daidzein. Therefore, the self-microemulsion drug delivery system (SMEDDS) was introduced to increase the solubility of daidzein and avoid the first pass effect. Whey protein isolate (WPI) was added as a precipitation inhibitor to SMEDDS (WD-SMEDDS) to inhibit daidzein crystallization and improve system stability. The final formulation was TPGS and Tween 20 as mixed surfactants, PEG400 as cosurfactant and ethyl oleate as oil phase to prepare WD-SMEDDS. The stability studies revealed that mixed surfactants were superior to single, and remained stable for at least 3 months. WD-SMEDDS showed excellent dissolution behavior that more than 90% and 80% of daidzein was released in pH 6.8 and pH 1.2, respectively. Therefore, protein-based SMEDDS might be an effective strategy for the oral administration of Dai and would be a potential system to deliver hydrophobic bioactive compounds.