In this research, the amoxicillin (AMX) removal was studied on a prepared nanosorbent from MOFs. The aim of this research work is to prepare nanohybrids based on metal–organic frameworks (MOFs) as an efficient nanosorbent for the absorption of amoxicillin drug. In this study, UIO-66 nanoparticles (UIO-66 NPs) were prepared from Zirconium (Zr) metal and 1,4-benzene dicarboxylic acid (BDC). Then UIO-66@Cr-MIL-101 nanohybrid was synthesized by hydrothermal method. Structural and physicochemical properties of nanohybrid UIO-66@Cr-MIL-101 were characterized by different analyses such as X-ray diffraction analysis (XRD), fourier transform infrared spectrometer (FT-IR), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM), therapeutic goods administration (TGA), and Brunauer–Emmett–Teller (BET). The effect of four fundamental variables effective on adsorption was optimized by the central composite response surface methodology (CCRSM). This parameters including loading percentage of Cr-MIL-101 NPs (10–30%), initial concentration of AMX (20–140 mg L−1), contact time (20–60 min), and pH (20–10). The removal percentage (Re%) of AMX equal to 99.50% was obtained under the following conditions: The loading value of 20% Wt%, the initial concentration of AMX 80 mg L−1, contact time 20 min, and pH = 6. Also, the experimental data were investigated with famous kinetic models and isotherms, and it was observed that AMX removal by nanohybrid is correlated with the PSO kinetic model and Langmuir isotherm.