Glioblastoma is the most common malignant brain tumor with a high grade of recurrence, invasiveness, and aggressiveness. Currently, there are no curative treatments; therefore, the discovery of novel molecules with anti-tumor activity or suitable drug delivery systems are important research topics. The aim of the present study was to investigate the anti-tumor activity of Givinostat, a pan-HDAC inhibitor, and to design an appropriate liposomal formulation to improve its pharmacokinetics profile and brain delivery. The present work demonstrates that the incorporation of Givinostat in liposomes composed of cholesterol and sphingomyelin improves its in vivo half-life and increases the amount of drug reaching the brain in a mouse model. Furthermore, this formulation preserves the anti-tumor activity of glioblastoma in 2D and 3D in vitro models. These features make liposome-Givinostat formulations potential candidates for glioblastoma therapy.