The objective of this study was to integrate inorganic halloysite nanotubes (HNT) with chitosan and hyaluronic acid to obtain hybrid nanocomposites with opposing charges and to investigate their potential in the controlled release of drug model probes. Two oppositely charged polysaccharides, chitosan and hyaluronic acid, were selected for their biocompatibility and their importance in biomedical applications. The high surface area and the hollow nanometric-sized lumen of HNT allowed for the efficient loading of rhodamine 110 and carboxyfluorescein, used as models for oppositely charged drugs. In the case of chitosan, the preparation of the nanocomposite was carried out exploiting the electrostatic interaction between the polymer and HNT in water, while with hyaluronic acid, a covalent functionalization strategy was employed to couple the polymer with the clay. Nanocomposites were characterized with thermal, microscopic, and spectroscopic techniques, and the release kinetics of the model compounds was assessed by fluorescence measurements. The release curves were fitted with a model able to account for the desorption process from the external and the internal halloysite surfaces. The results show that both polymeric coatings alter the release of the probes, indicating a key role of both charge and coating composition on the initial and final amount of released dye, as well as on the rate of the desorption process.