Silibinin is considered as a functionalized flavonoid and natural substitute for synthetic anticancer drugs like doxorubicin, paclitaxel, etc. However, the principle reasons for restraining the bioavailability of silibinin are low aqueous solubility, less penetration into the epithelial cells of the intestine and rapid systemic elimination. This present work focused on the development of inclusion complexes of silibinin with hydroxypropyl-β-cyclodextrin and further incorporated into hybrid liposomes to improve solubility, bioavailability and stability as well as to explore the anticancer activity of silibinin. Hybrid liposomes were prepared by thin lipid film hydration method. Molecular docking studies projected for the formation of complex with physicochemical structural changes which were confirmed by ATR-FTIR, DSC, XRD, ¹H NMR and SEM studies. The particle size distribution of hybrid liposomal formulations was obtained in the range of 200–500 nm with zeta potential more than – 30 mV. The release of silibinin from hybrid liposomes was maximum (75.40% ± 0.73) with better solubility (73.95 mg/mL) and relative bioavailability (4.52). This drug delivery system exhibited higher cytotoxicity against kidney cancer cell line (A-498) through endocytic internalization into the cells and good pharmacokinetic properties as compared with silibinin. In near future, hybrid liposomes can be a promising carrier for increasing the solubility, bioavailability and stability of silibinin.