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Abstract This study aimed to overcome the poor solubility of pterostilbene (PTS) by developing promising reconstituted proethoniosomes (PENs). The reconstituted PENs loaded with PTS were fabricated according to a 23 factorial design by Design-Expert® software. The prepared ethoniosomes were assessed for entrapment efficiency (EE %) and % PTS released after 24 h (Q24h). According to the desirability criteria, the ethoniosomal formula (F4) was chosen as the optimized formulation with EE% of 93.19 ± 0.66 and Q24h of 75.10 ± 1.90%. The optimum ethoniosomal formulation was further coated with folic acid (FA) using bovine serum albumin (BSA) as a carrier and stabilizing agent and further evaluated for transmission electron microscopy (TEM), particle size, zeta potential, elasticity, Fourier transform infrared spectroscopy (FTIR), and stability. The targeted ethoniosomal formula appeared as spherical nanovesicles with a size of 144.05 ± 1.77 nm size and a zeta potential of -38.6 mV. The elasticity of the targeted ethoniosomal formula 19.27 ± 1.2 was higher than that of the corresponding niosome 1.48 ± 0.02. The targeted ethoniosomal formula showed high stability for three months. Fluorescence microscopy demonstrated an accumulation of FA-BSA-ethoniosomes in the cytoplasm of A549 cell lines. The observed therapeutic activity of the targeted ethoniosomal formula on lung cancer was explored by in vitro cytotoxicity on A549 lung cancer cells and in vivo animal models. The in vivo results were supported by histopathological analysis and immunohistochemical caspase-3 staining. FA-BSA-ethoniosomal formulation allowed specific targeting of cancer tissues overexpressing folate receptors. Overall, these results confirmed that the targeted ethoniosomal formula could be a promising nano-carrier for potential application as targeted cancer chemotherapy in clinical studies. Graphical Abstract