The poor water solubility and bioactivity of lipophilic phytochemicals can be potentially improved by delivery systems. In this study, a low-cost, low-energy, and organic solvent-free encapsulation technology was studied by utilizing the pH-dependent solubility properties of curcumin and self-assembly properties of sodium caseinate (NaCas). Curcumin was deprotonated and dissolved, while NaCas was dissociated at pH 12 and 21 °C for 30 min. The subsequent neutralization enabled the encapsulation of curcumin in self-assembled casein nanoparticles. The degradation of curcumin under encapsulation conditions was negligible based on visible light and nuclear magnetic resonance spectroscopy. The dissociation of NaCas at pH 12 and reassociation after neutralization were confirmed using dynamic light scattering and analytical ultracentrifugation. The curcumin encapsulated in casein nanoparticles showed significantly improved anti-proliferation activity against human colorectal and pancreatic cancer cells. The studied encapsulation method is promising to utilize lipophilic compounds in food or pharmaceutical industries.