Trace pharmaceutical concentrations are commonly found in wastewater worldwide. The high polarity of these pollutant molecules and their low concentrations in the order of micro- nanograms per liter make them difficult to remove by conventional separation units installed in wastewater treatment plants and advanced purification processes. The accumulation of these pollutants in ecosystems has become a critical issue because they pose major threats to flora, fauna, and human health. Diclofenac (DCF) is a pharmaceutical product that belongs to this category, and its adsorption onto clay minerals, notably kaolin, provides an economical and effective approach for addressing wastewater pollution. In this study, kaolin modified with cetylpyridinium chloride (K-CPC) was characterized and evaluated for DCF removal. This modified clay sample had a surface area, pore size, and volume of 5.57 m2/g, 191.6 Å and 0.03 cm3/g, respectively. Under the best operating conditions, 93.53% removal and 392.3 µg/g of DCF adsorption capacity were obtained. Redlich-Peterson and pseudo-second-order equations correlated the pharmaceutical adsorption data. The estimated DCF adsorption enthalpy was −27.87 kJ/mol, which corresponds to an exothermic process. Advanced modelling based on statistical physics was used for a steric analysis of the DCF adsorption mechanism, concluding that it was multi-molecular. DCF adsorption on K-CPC involves physical adsorption, in which hydrogen bonding, π – π interactions, and electrostatic forces play important roles in the removal mechanism. Thus, DCF removal from polluted streams in large-scale applications using this new adsorbent is promising.