In the present project, we have applied a molecular imprinted polymer (MIP) for the solid phase extraction (SPE) of quetiapine residue from human blood plasma. This study aimed to develop a method for determination of the bioavailability of quetiapine as a widely used antipsychotic in the blood serum. The extraction of quetiapine from the plasma was optimized and the loading amount (LA) for its adsorption was determined. Subsequently, a HPLC-UV/VIS method was validated and applied to analyze the concentration of the mentioned drug which was extracted from the blood serum. The results showed that the limit of detection (LOD), and the limit of quantification (LOQ) for the validated MIP-SPE approach were about 0.0172 ng ml À 1 , and 0.0481 ng ml À 1 , respectively. Finally, each of the MIP, and the non-imprinted polymer (NIP), and their complex with the guest drug were designed and optimized by the density functional theory (DFT) approach. Based on our theoretical calculations, the structural properties, as well as the reactivity parameters (the molecular descriptors) were extracted, and debated. The results of the theoretical calculations showed a good agreement with the experimental results. Those results confirmed the favorability of adsorption of the drug by MIP compared to NIP.