Squalene epoxidase (SQLE) is a crucial enzyme in the cholesterol-biosynthesis pathway and a promising target for treating cholesterol-related disorders. This study aimed to repurpose eighteen clinically approved phenothiazine antipsychotics as competitive SQLE inhibitors by integrating structure-based virtual screening, 200 ns molecular-dynamics simulations, MM/PBSA binding-energy calculations and in vitro enzyme assays. We first screened the 18 derivatives using molecular docking, structural/pharmacological diversity and ADMET analysis. Six compounds-ethopropazine, periciazine, piperacetazine, dixyrazine, fluphenazine and trifluoperazine-were prioritized for detailed MD simulations and MM/PBSA evaluation. Potential-energy-landscape analysis revealed that ethopropazine, periciazine and piperacetazine formed the most stable enzyme-ligand complexes, each occupying well-defined energy wells. Corresponding ΔGtotal values of - 27.05 ± 2.10 kcal mol⁻¹, - 27.84 ± 1.67 kcal mol⁻¹ and - 26.94 ± 1.82 kcal mol⁻¹ indicated high binding affinities. In vitro assays confirmed potent SQLE inhibition, with IC₅₀ values of 1.69 ± 0.06 µM, 1.55 ± 0.13 µM and 1.44 ± 0.04 µM, respectively; kinetic studies established competitive inhibition with Ki values of 0.65-0.69 µM. The strong correlation between computational predictions and experimental data underscores the effectiveness of our integrated approach and identifies ethopropazine, periciazine and piperacetazine as promising lead compounds for further optimization and pre-clinical development as SQLE inhibitors.