Adsorption characteristics of high-silica zeolites (HSZSM-5) for two selected sulfonamide antibiotics (SAs) (sulfamethoxazole and sulfadiazine) were investigated. The SAs were almost completely (>90%) removed from the water by HSZSM-5. Adsorption followed second-order kinetics with liquid–film diffusion as the dominant mechanism. SA adsorption capacity on high-silica zeolites was examined in terms of pH, temperature, and the presence of natural organic matter (NOM). HSZSM-5 had better adsorption performance in acidic conditions, and the apparent distribution coefficient indicated that SA0 species were the major contribution to the overall adsorption at pH of 2–10. Adsorption of SAs on HSZSM-5 was a spontaneous and exothermic physisorption process. SA removal by HSZSM-5 was a mixed mechanism through ion-exchange and hydrophobic interaction. HSZSM-5 has potential application prospects in removing SAs from wastewater.