<p>Lenvatinib (LNVT), a brick dust molecule, has shown promising results in treating a range of cancers. Nonetheless, its effectiveness is limited by its poor solubility and low bioavailability. In this study, we fabricated the inclusion complex of LNVT with 2-hydroxypropyl-β-cyclodextrin (LNVT-HPCD IC) to enhance the physicochemical and therapeutic potential of LNVT. The developed inclusion complex was characterized through UV spectroscopy, FT-IR, SEM, DSC, and PXRD studies. ¹H NMR of the inclusion complex showed a significant change in the chemical shift values of the proton of LNVT when compared to the PM. Findings from the ITC revealed the binding affinity between LNVT and 2-hydroxypropyl-β-cyclodextrin (HPCD). An in silico study showed a high negative binding energy of LNVT for both β-cyclodextrin and HPCD. The phase solubility and Job’s plot demonstrated 1:1 stoichiometry between LNVT and HPCD. The aqueous solubility revealed approximately 13.74-fold greater solubility when compared to free LNVT. Furthermore, both in silico and in vitro approaches were used to evaluate the therapeutic activity of LNVT and its complex in the PA-1 ovarian teratocarcinoma cell line. MTT assay demonstrated higher cytotoxicity in PA-1 ovarian cancer cells from the LNVT-HPCD IC-treated group compared to the free LNVT solution. Nonetheless, microscopy imaging, DAPI staining and western blotting results of PARP-cleavage further confirmed the cytotoxic and apoptosis inducing potential of LNVT-HPCD IC compared to free LNVT in ovarian cancer cells. In a nutshell, the inclusion complex of LNVT with HPCD is an effective approach to overcoming the pitfalls associated with the free LNVT. </p> Graphical Abstract <p></p>