Organoclays have been applied as efficient adsorbents for pharmaceutical pollutants from aqueous solution. In this work, dodecylpyridinium chloride (C12pyCl) and hexadecylpyridinium chloride (C16pyCl) cationic surfactants were used for the preparation of organobentonites destined for diclofenac sodium (DFNa) adsorption, an anionic drug widely detected in wastewater. The organofunctionalization of the clay samples was performed under microwave irradiation at 50 °C for 5 min with surfactant amounts of 100% and 200% in relation to the cation exchange capacity (CEC) of the pristine bentonite. The amount of incorporated ammonium salts based on CHN elemental analysis was higher for all samples prepared with 200% of the CEC. The basal spacings of the organoclays ranged from 1.54 to 2.13 nm, indicating the entrance of organic cations into the interlayer spacing of the clay samples, and the spacing depended on the size of the alkyl organic chain. The hydrophobic character of the organobentonites was verified by thermogravimetry and infrared spectroscopy (FTIR). The adsorption isotherms showed that the drug capacity adsorption was influenced by the amount of surfactant incorporated into the bentonite, the packing density and the arrangement of the surfactants in the interlayer spacing. Zeta potential measurements of the organobentonites and FTIR analysis after drug adsorption suggested that electrostatic and nonelectrostatic interactions contributed to the mechanism of adsorption.