Erythromycin (ERY), an antibiotic widely used in human and veterinary medicine, persists in the environment due to its low degradability, accumulating in wastewater and soil. This study presents a novel adsorbent synthesized by magnetically modifying calcined natural bentonite with Fe₃O₄ nanoparticles to enhance ERY removal. The modification increased the surface area, with the highest adsorption observed at pH 11. Adsorption studies revealed that the Dubinin–Radushkevich isotherm model and pseudo-first-order kinetic model best described the adsorption behavior. Response surface methodology (RSM) was employed to optimize key parameters, including adsorbent dosage, temperature, and contact time. The quadratic model indicated optimal conditions of 41.9 mg adsorbent, 29.1 °C, and 9.6 h of contact time, yielding a maximum ERY removal efficiency of 96.2%. Density functional theory (DFT) analysis provided a molecular-level understanding of the adsorption mechanism, identifying strong interactions between ERY, Fe₃O₄, and bentonite. The theoretical binding energy aligns with experimental results, confirming the role of magnetic modification in promoting ERY adsorption. This study demonstrates a promising approach for mitigating ERY contamination in aqueous environments.