Curcumin and piperine are natural nutraceuticals that exhibit synergistic biological activities, but have different polarities, which can make their encapsulation within a single delivery system challenging. In this study, the two bioactive components were encapsulated within core-shell nanoparticles formed by a combination of antisolvent precipitation and layer-by-layer deposition. Initially, strongly hydrophobic curcumin (log = 4.12) was embedded in the hydrophobic core of zein-hyaluronic acid nanoparticles using the antisolvent precipitation method. Then, the weakly hydrophobic piperine (log = 2.78) was adsorbed to the outer biopolymer shell of these nanoparticles. Finally, the nutraceutical-loaded particles were coated with a layer of chitosan by the electrostatic deposition method. The surface charge and coating thickness depended on the number of adsorbed layers and the nature of the outer layer, being negative for hyaluronic acid and positive for chitosan. Low-, medium-, and high-molecular weight chitosan were utilized to modify the surface properties. Chitosan with a low-molecular weight was selected to fabricate the core-shell nanoparticles because it produced small highly charged cationic particles ( = 599 nm; ζ = +38.1 mV). The encapsulation efficiency and loading capacities were 90.4 and 5.7% for curcumin, and 86.4 and 5.4% for piperine, respectively. The core-shell nanoparticles protected the nutraceuticals from chemical degradation during light exposure, thermal processing, and storage for 2 months. Moreover, the nanoparticles were able to control the release of the bioactive components in simulated gastrointestinal conditions. Our results should facilitate the development of more effective nanodelivery systems for nutraceuticals that exhibit synergistic activities, but have different molecular characteristics.