Abstract Vitexin, known for its potent bioactive properties, suffers from low bioavailability due to poor water solubility, limited intestinal permeability, and extensive first‐pass metabolism. This research aimed to address these challenges by developing effective delivery systems for vitexin. Vitexin was nanoencapsulated with mung bean protein isolate (MBPI), both in its native form and after ultrasound‐assisted pH‐shifting treatments at pH 10 and 12. Additionally, vitexin‐loaded MBPI nanoparticles were coprecipitated with calcium carbonate (CaCO 3 ) to form nano‐in‐microparticles. Ultrasound‐assisted pH shifting, particularly at pH 12, induced protein unfolding and increased surface hydrophobicity, which enhanced hydrophobic interactions between MBPI and vitexin and improved encapsulation efficiency. During in vitro gastrointestinal digestion, the ultrasound‐assisted pH‐shifted MBPI nanoparticles exhibited a lower degree of hydrolysis (DH) compared to native MBPI nanoparticles. Their integration into CaCO 3 microparticles further reduced DH values. The release of vitexin from MBPI nanoparticles prepared at pH 12 and then encapsulated in CaCO 3 microparticles followed the Korsmeyer–Peppas model, with a particle size of 40.14 nm and a high logarithmic partition coefficient between n ‐octanol and phosphate buffer saline (1.91) at the end of digestion. These findings indicate that this delivery system holds significant potential for enhancing the intestinal permeability and bioavailability of vitexin.