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Background: Perphenazine (PPZ) is a prevalent antipsychotic medication used to treat schizophrenia. After oral treatment, however, it shows substantial first-pass metabolism and decreased bioavailability. Objective: The goal of this research was to incorporate PPZ into nanostructured lipid carriers and thereby improve its bioavailability and brain targeting (PPZ-NLCs). Method: PPZ-NLCs were formulated by a high-pressure homogenization methodology under heated conditions and optimized by applying a 23-full factorial design. Results: The optimized PPZ-NLCs showed particle size 167.5 nm, PDI 0.277, Zeta Potential of -28.8 mV, and 98.6% EE. The drug release during In-vitro experiments of PPZ-NLCs exhibited a prolonged release profile of the drug best fitted into the Higuchi kinetic model. PPZ-NLCs when examined In-vivo pharmacokinetically a significant increase in t1/2, AUC0-∞, and Cmax was observed which indicates a greater bioavailability and a lesser elimination (Kel). Conclusion: These results suggested the superiority of NLCs in enhancing the bioavailability of PPZ drug and their suitability for successful brain targeting.