A molecular modeling approach was used to elucidate template-monomer interaction and the effect of solvent on the recognition of molecularly imprinted polymers (MIPs). Ciprofloxacin (CIP) was taken as the template molecule. The methacrylic acid (MAA), 4-vinyl pyridine (4-Vpy), acrylamide (AAM), and 2-(trifluoromethyl) acrylic acid (TFMAA) were taken as the functional monomers, respectively. Density functional theory (DFT) at the LC-WPBE/6-31g(d,p) level has been adopted to investigate the geometry optimization. The NBO charge and the binding energies of CIP with the monomers were carried out. The molecular imprinting mechanism of CIP and the monomers as well as the influence of solvent was also discussed. Results indicate that CIP and the monomers are matchable in steric structure and chemical groups lead to ordered compounds. The interaction between CIP and TFMAA is the strongest, and when the ratio of CIP-TFMAA is 1:6, the polymer has the lowest energy in toluene. The computational approach has been applied to provide details of interactions between CIP and the monomers. This research will hopefully shed light on the future study of CIP-MIPs. A molecular modeling approach was used to elucidate template-monomer interaction and the effect of solvent on the recognition of molecularly imprinted polymers (MIPs). Ciprofloxacin (CIP) was taken as the template molecule. The methacrylic acid (MAA), 4-vinyl pyridine Density functional theory (DFT) at the LC-WPBE / 6-31g (d, p The scale has been adopted to investigate the geometry optimization. The NBO charge and the binding energies of CIP with the monomers were carried out. The molecular imprinting mechanism of CIP and the monomers as well as the influence of solvent was also discussed. Results indicate that The interaction between CIP and TFMAA is the strongest, and when the ratio of CIP-TFMAA is 1: 6, the polymer has the lowest energy in toluene. The CIP and the monomers are matchable in steric structure and chemical groups lead to the ordered compounds. computational a pproach has been applied to provide details of interactions between CIP and the monomers. This research will hopefully shed light on the future study of CIP-MIPs.