Despite having good efficacy in the treatment and prevention of tuberculosis, the administration of rifampicin (RIF) can cause serious side effects, resulting from the prolonged use of this substance. Thus, it is necessary to seek new systems for administering tuberculostatic drugs, to avoid unwanted adverse effects, increase their bioavailability and, consequently, improve their therapeutic efficacy. The present work describes the achievement of a pH-responsive system for RIF, using palygorskite, a fibrous clay mineral, as a nanocarrier. To evaluate the influence of some operational variables on the drug adsorption process, a 2(4) factorial experimental design was used. The experiment using a maximum concentration (0.125 mg/mL), lower mass of PAL (300 mg), and lower pH (pH 2) was more efficient compared to other experiments, resulting in a higher dose of the incorporated drug, equivalent to 33.62 mg/g. To elucidate the mechanism of interaction between the materials, the hybrid obtained was characterized by different characterization techniques (Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetry/derived thermogravimetry, zeta potential, scanning electron microscopy, and dispersive energy spectroscopy). In addition, kinetic models and adsorption isotherms were applied to the experimental data. Through in vitro release studies, it was possible to verify the effectiveness of the pH-dependent system obtained. The adjustment of experimental release data to the theoretical model of Higuchi indicated that the release of rifampicin occurs in a prolonged way from the palygorskite.