<p>The development of efficient and cost-effective catalytic systems for antibiotic degradation remains a significant challenge in environmental remediation. Herein, a novel Co/CuFe₂O₄ composite was synthesized via a sol–gel combustion method to construct a multi-metal synergistic photocatalytic-Fenton-like system for the degradation of oxytetracycline (OTC). Density functional theory (DFT) calculations indicate that the incorporation of Co leads to a more negative material formation energy, suggesting that Co/CuFe₂O₄ has a more stable electronic structure. This optimized electronic structure enhances the redox cycle (Fe³⁺/Fe²⁺, Cu²⁺/Cu⁺, and Co²⁺/Co³⁺), thereby improving the activation efficiency at low concentrations of H₂O₂ (0.1–6&#xa0;mmol/L). Under optimal conditions (pH 3, 35 °C, 4 mmol/L H₂O₂), the 13% Co/CuFe₂O₄ catalyst achieved complete OTC degradation within 60 min, with an 0.1 mmol/L H₂O₂ utilization rate of 17.81% at neutral pH. Moreover, the catalyst exhibited excellent stability, retaining 87.5% degradation efficiency after five cycles. Radical quenching experiments confirmed that ·OH, h⁺, and ·O₂⁻ were the dominant reactive species, while the synergistic effect of multiple metal redox pairs facilitated efficient electron transfer and H₂O₂ activation. This work provides a promising strategy for designing high-performance Fenton-like catalysts with broad pH adaptability and low oxidant consumption, offering significant potential for the treatment of antibiotic-contaminated wastewater.</p> Graphical Abstract <p></p>