The present study focused on developing and evaluating chitosan-coated liposomal vesicles as a transdermal drug delivery system for granisetron hydrochloride, a potent antiemetic drug used in chemotherapy-induced nausea and vomiting Minitab 21.4 software was used to optimize granisetron delivery systems through a 4-factor, 2-level full factorial design. This investigation focused on key formulation factors: preparation method, drug/lipid fraction, lecithin type, chitosan coating, and their impact on critical responses. This approach helped to identify factors of high significance in the model equation, enhancing the understanding of granisetron formulation optimization.. Physicochemical properties, drug release profile, release kinetics, and ex vivo skin permeation studies were conducted to assess the liposomal formulations. The optimization process aimed to achieve specific targets, including a particle size of approximately 120 nm and a zeta potential of +35 Ve. The chosen optimal formulation exhibited favorable values, with an entrapment efficiency of 47.29% ± 2.23 , particle size of 137.25 nm± 5.72 , zeta potential of 17.14 Ve ± 1.71 , and dissolution efficiency of 86.82%± 7.68 . Further, The optimized liposomal gel formulation demonstrated a 25% increase in flux (27.73 μg.cm-2.hr-1) compared to the raw drug-loaded gel (22.03 μg.cm-2.hr-1) for the permeation of granisetron through the skin. These findings underscored the superior drug delivery capabilities of the liposomal systems and their potential for improving therapeutic outcomes in the targeted application. The results indicated that the liposomal-loaded formulations had the potential to enhance the transdermal delivery of granisetron compared to conventional gel formulations.