In the present work the incorporation of two model drugs, sulfamethoxazole (SMX) and trimethoprim (TMP) on the Li-fluorohectorite (LiFHt), synthetic clay mineral was evaluated. Understanding the interactions established between these two antibiotics – which are complementary forms from the pharmaceutical point of view – and LiFHt, allows to develop new drug delivery formulations with both drugs in the same support. The quantification of both drugs was followed by ultraviolet (UV) spectroscopy. For the interaction clay mineral-drugs, different physical-chemical parameters−pH, drug initial concentration, temperature and interaction time−were studied. The results showed that, for both drugs, the best clay mineral-drug nanocomposites were obtained at acid pH, room temperature during 1 h, and initial drug concentration of 3 mg/mL. The resulting clay mineral-drug nanocomposites were characterized by X-ray diffraction (XRD), infrared (IR) spectroscopy and thermal gravimetry (TG). It was corroborated by XRD that the TMP was truly intercalated into the clay mineral. However, SMX seems to be adsorbed onto the clay mineral surface. For the LiFHt-TMP nanocomposite, IR suggested clay mineral-drug interactions via amine groups of the TMP. No significant changes in the IR spectrum for the LiFHt-SMX were observed. The drug release profiles showed to follow the pharmaceutical standards, and suggested the possibility to design formulations of drug delivery using LiFHt as carrier.