This study investigates the synergistic effect of silver on the anticancer activity of doxorubicin (DOX) encapsulated in silver-integrated amino-functionalized silica nanoparticles (AFS-NPs) coated with chitosan (DOX@AFS-NPs-Ag-CS). AFS-NPs were synthesized by a co-condensation approach using tetraethyl orthosilicate (TEOS) and 3-aminopropyltriethoxysilane (APTES) with cetyltrimethylammonium chloride (CTAC) as a template, followed by silver incorporation through silver nitrate (AgNO
3
) treatment in dark conditions. Doxorubicin was subsequently loaded and stabilized by chitosan (CS) coating. Morphological analysis by scanning electron microscopy (SEM) confirmed spherical, uniform nanoparticles (∼900nm), while X-ray diffraction (XRD), Fourier transform infrared (FTIR), UV-Visible spectrophotometry, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) verified successful synthesis and drug encapsulation. Thermal stability enabled the physical encapsulation of DOX and conferred suitable thermal stability to the formulation for anticancer studies. The formulation showed a drug loading content (LC) of 17% and an entrapment efficiency (EE) of 84%. Release studies revealed pH-responsive release of DOX, achieving ∼94.2% in 24 h under acidic conditions. Importantly, DOX@AFS-NPs-Ag-CS demonstrated significant anticancer activity (60.18% inhibition) against Hep G2 cancer cell lines. These results highlight the potential of this hybrid nanocarrier for effective and targeted cancer therapy.