Glioblastoma (GBM) is the most frequent and lethal primary brain tumor, rapidly growing and spreading into nearby healthy tissues with devastating effects for patients and those around them. GBM has currently no cure, being the average survival of GBM patients after diagnosis limited to a few months. The drug resistance ability and fast regrowth of GBM are the main problems related to current treatments. The intrinsic high heterogeneity and the microenvironment of these tumors are some of the reasons for the low efficacy of the available treatments. Therefore, new therapy alternatives for this highly aggressive brain cancer are urgently needed. Chalcones are synthetic or naturally occurring compounds that have been widely investigated for cancer targeting. Thus, in this work, chalcone derivatives were tested regarding their inhibitory activity and specificity toward GBM cell lines. The chalcone derivative with the most potent and selective cytotoxic effects on GBM cells was further investigated regarding its ability to reduce critical hallmark features of GBM. This derivative showed to successfully reduce key targets for cancer treatment, namely the invasion and proliferation capacity of tumor cells by inducing cell cycling arrest and cell apoptosis. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was successfully encapsulated into liposomes. Therapeutic concentrations were incorporated re-taining the potent in vitro growth inhibitory effect of the selected chalcone. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.