Background/Objectives: Curcumin (CUR) is a potent anticancer agent whose clinical application is hindered by its extremely poor aqueous solubility. This study reports the development of enzyme-responsive whey protein isolate (WPI) nanoparticles for CUR targeted delivery. Methods: To overcome the initial solubility barrier, CUR was first formulated as a solid dispersion with WPI using freeze-drying. This process resulted in a significant enhancement in aqueous solubility (up to 1478-fold), with CUR existing in molecular dispersion or in an amorphous state within the protein matrix as confirmed by Differential Scanning Calorimetry (DSC) and Fourier-transform infrared (FT-IR) spectroscopy. The solubilized CUR-WPI solid dispersion was subsequently used to generate nanoparticles via a thermal gelation method, avoiding the use of organic solvents or toxic chemical crosslinkers. Results: The resulting nanoparticles exhibited a high drug loading efficiency of 85%. In vitro release studies demonstrated minimal CUR release in physiological buffer (pH 7.4) over 24 h, whereas exposure to trypsin, a nonspecific serine protease used as an in vitro model for tumor-associated proteolytic activity, triggered rapid nanoparticle degradation and released 95% of CUR within 3 h. Conclusions: These findings suggest that WPI-based nanoparticles developed from solid dispersions offer a promising, biocompatible platform for the solubility enhancement and protease-triggered delivery of hydrophobic anticancer drugs.