Chitosan/alginate nanoparticles (CANPs) were formulated to encapsulate curcumin diethyl diglutarate (CDG) for oral delivery. CDG-loaded CANPs (CDG-CANPs) were prepared by o/w emulsification and ionotropic gelation. The optimization of CDG-CANPs was successfully performed by response surface methodology. The characteristics including photostability, storage stability, digestive stability, in vitro digestibility, bioaccessibility and in vitro uptake in Caco-2 cells of free CDG and CDG-CANPs were investigated. The optimal CDG-CANPs could be prepared by chitosan/alginate mass ratio of 0.065:1, 1% (w/v) Pluronic®F127 and 4.5 mg/mL of CDG. The optimized nanoparticles had the particle size, zeta potential, encapsulation efficiency and loading capacity of 215 nm, -24.1 mV, 85% and 27%, respectively. The CDG-CANPs showed better stability under UV irradiation and thermal exposure compared with free CDG. The CDG-CANPs had stability up to 3 months at 4 °C. The in vitro release profile showed sustained-release manner and best fit with the Korsmeyer-Peppas kinetic model, indicating the Fickian diffusion mechanism. Nanoparticle encapsulation significantly enhanced in vitro digestibility and bioaccessibility under simulated gastrointestinal conditions and cellular uptake of CDG. The overall results suggest that CANPs are promising candidates for encapsulation, protection and controlled release of CDG, a hydrophobic compound, with an improvement of physicochemical stabilities, digestibility, bioaccessibility and cellular uptake.