Abstract: The widespread residues of quinolone antibiotics in water environments have posed serious ecological safety risks. For ciprofloxacin (CIP), a typical antibiotic with high detection frequency, the adsorption and fate mechanisms at the sediment-water interface of the Weihe River remain unclear. This study selected CIP as the target pollutant and focused on sediments from the Weihe River. The adsorption behavior and mechanisms of CIP on sediments were revealed through batch equilibrium experiments, combined with kinetic and isotherm models, microscopic characterization, and density functional theory (DFT) calculations. The results indicated that the adsorption kinetics followed the pseudo-second-order kinetic model (R²>0.999), and the adsorption and desorption behaviors were jointly regulated by multiple mechanisms, with significant hysteresis in desorption. The thermodynamic fitting results showed that the Freundlich model provided the best fit (R²>0.968), indicating that the adsorption process of CIP on sediments was simultaneously affected by multilayer adsorption on heterogeneous surfaces and hydrophobic partitioning, and that increasing the temperature had an inhibitory effect on the adsorption process. Characterization analysis demonstrated that pore filling, surface complexation, π—π interactions, and hydrogen bonding collectively contributed to the adsorption process. Among them, mineral components (SiO₂, Al₂O₃, and Fe₂O₃) served as the primary active sites, and the contribution of Fe₂O₃ was particularly prominent (70.2%). DFT calculations revealed the differences among components at the molecular level: SiO₂ was mainly bound by hydrogen bonds, while Fe₂O₃ and Al₂O₃ were mainly governed by surface complexation, with Fe₂O₃ having the highest adsorption energy (−9.722 eV). This study elucidates the multi-mechanism synergistic process of CIP adsorption on sediments, providing a theoretical basis for accurately predicting the migration and fate of antibiotics in the environment.