<p>Persulfate-based advanced oxidation processes (PS-AOPs) have emerged as leading candidates to combat organic pollutants in wastewater. Thus, developing an efficient catalytic degradation can be a suitable solution for removing recalcitrant organic pollutants. This study describes the fabrication and characterization of the <i>γ</i>-Fe₂O₃@SiO₂/CuO-MoO₃ (F@S/C-M) nanocomposite as an ammonium peroxydisulfate (NH₄PDS) activator for the degradation of organic pollutants. Importantly, the SiO₂ coating on the surface of maghemite prevents the agglomeration of iron NPs and leads to a suitable junction of CuO and MoO₃ to the silicon surface. Furthermore, the presence of iron, copper, and molybdenum elements in the nanocomposite enables excellent NH₄PDS activation to generate reactive oxygen species (ROS). The F@S/C-M/NH₄PDS system achieved degradation efficiencies of 99.4%, 97.1%, and 87.7% for organic dyes, including methylene blue (MB), malachite green (MG), and indigo (IN), respectively. It maintains over 95% efficiency after multiple cycles in MB, demonstrating catalytic stability and reusability. Among the ROS produced in this system, <InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\:{\text{S}\text{O}}_{4}^{{\bullet\:}-}\)</EquationSource> </InlineEquation>, ^•OH, and ^•<InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(\:{\text{O}}_{2}^{-}\)</EquationSource> </InlineEquation> radicals contributed the most to organic dye degradation due to the excellent activation of NH₄PDS, which was confirmed by scavenging tests. Control experiments reveal that the proposed nanocomposite benefits from a synergistic effect of all the components being present in the same hybrid system. Additionally, density functional theory (DFT) calculations were employed to investigate the relationship between pollutants’ molecular structure and degradation rates. The present study provides a rational design and synthesis of multifunctional catalysts for various applications.</p>