In this study, raw kaolin clay was activated with a strong base solution in order to improve its surface characteristics and adsorption performance. The alkali activation evidently caused etching process and ion exchanges of both Al3+ and Si4+ with Na+ on the silica and gibbsite basal surfaces, enhancing the surface area of the kaolinite particles. Adsorption of rifampicin (RIF) on the raw and alkali-activated kaolin was well described by the Langmuir isotherm and the pseudo-second-order kinetics models. The maximum adsorption capacity of RIF on the alkali-activated kaolin was 8.295 mg g−1, enhanced compared with the raw kaolin (5.931 mg g−1). The adsorption was due to weak electrostatic and hydrogen bonding interactions between RIF and the kaolinite surfaces. Adsorption mechanism, kinetics, rate limiting-step, and thermodynamics were described in detail by fitting mathematical functions of the established semiempirical models to the experimental data. The recyclability of the kaolin-based adsorbents was demonstrated by their effective regeneration. Overall, the alkali activation improves the adsorption performance of kaolin to be practically applicable as environmentally friendly and sustainable absorbents for the removal of RIF and probably other pharmaceutical compounds from hospital wastewater.