Background <p>Head and neck squamous cell carcinoma (HNSCC) is a major and growing public health problem due to its global high incidence and mortality. Most conventional treatments have adverse side effects due to lack of selectivity and targetabiliy, which has increased the demand for more precise and safe alternatives. Amygdalin (AMG) is a plant-derived cyanoglycoside with a potent anticancer effect, however, its therapeutic use remains controversial due to safety concerns.</p> Objective <p>Nanotechnology can improve the targeted delivery of AMG while reducing its drawbacks. This study aimed to develop a nanocomposite comprised of chitosan (CS), reduced graphene oxide (rGO), zinc oxide nanoparticles (ZnO NPs), and hyaluronic acid (HA) to serve as a nanocomposite for controlled release and targeted delivery of AMG.</p> Methods <p>AMG-loaded (CS/rGO-ZnO/HA) nanocomposite was prepared by the ion gelation technique using tripolyphosphate (TPP) as a crosslinker. Blank and AMG-loaded nanocomposites were characterized using FTIR, XRD, TEM, SEM, DSC, and TGA. In vitro drug release was conducted via the dialysis bag method. In vitro anticancer effect of the prepared nanocomposite was evaluated via cell viability, wound scratch, and cellular uptake assays.</p> Results <p>AMG-loaded nanocomposite manifested a particle size of 180.2 ± 2.13&#xa0;nm with a negative surface charge of -36.5 ± 4.96 mV, high encapsulation efficiency (90.81%±1.23), and pH-dependent controlled release. Moreover, AMG-loaded nanocomposite exhibited a much lower IC₅₀ value in comparison to free AMG when examined against A-341 cells. In addition, AMG-loaded nanocomposite demonstrated improved anti-migratory effect, associated with enhanced cellular uptake due to its active targeting potential.</p> Conclusion <p>AMG-loaded nanocomposite could be considered a promising targeted nanoplatform for managing head and neck squamous cell carcinoma.</p>