In this study, natural clinoptilolite was modified by saponin and Brij 35 surfactants to remove diethylstilbestrol (DES) from wastewater in batch and continuous systems. The optimum pH, amount of adsorbent, contact time, and temperature were 11, 10 g/L, 12 h, and 35 °C, respectively, for the process. The equilibrium data agreed well with the Langmuir isotherm for natural clinoptilolite (NC), natural clinoptilolite modified by Brij 35 (NC-Brij), and natural clinoptilolite modified by saponin surfactants (NC-saponin) compared to other isotherms. The maximum adsorption capacities resulting from the Langmuir isotherm for NC, NC-Brij, and NC-saponin were 8.012, 23.64, and 39.525 mg/g, respectively. Fixed-bed column experiments were performed under various operational conditions to evaluate the performance of the adsorbent bed breakthrough curve. The lumped method solves bed equations to determine the axial dispersion coefficient (Dz) and overall mass transfer coefficient (Koverall) parameters. Comparison of the kinetic models indicated that the DES adsorption process was well described by the intraparticle diffusion model for NC, pseudo-second-order and fractional power kinetic models for NC-Brij, and pseudo-second-order model for NC-saponin. The negative Gibbs free energy and positive enthalpy changes for NC, NC-Brij, and NC-saponin confirmed that the removal reaction of DES was spontaneous and the adsorption was endothermic, respectively.