Schizophrenia is a complex mental illness that affects almost 1% of the population and has no curative treatment. Currently, available neuroleptic drugs have severe limitations and induce drug-related adverse effects. Receptor binding affinity parameters and lipophilicity are important characteristics that describe the bioactivity of these drugs. Lipophilicity is an important physicochemical property of a drug, which predicts distribution, binding to plasma protein, crossing the blood–brain barrier, and biological activity. Five antipsychotic drugs (Haloperidol, Risperidone, Aripiprazole, Olanzapine, and Quetiapine) were selected and the experimental determination of lipophilicity was carried out by reverse phase thin-layer chromatography (RP-TLC) using four types of stationary phases (RP-18, CN, Diol, and NH2 modified silica gel HPTLC plates) and acetonitrile-water with increasing percentage of acetonitrile and 0.2% formic acid in each case as mobile phase. Lipophilicity parameters (mRM and RM0) calculated from the experimental chromatographic retention data were discussed in terms of the correlation with different receptor binding affinity parameters determined by computational methods.