The purpose of the present investigation was to formulate NAC (N-acetylcysteine)-loaded chitosan (CH)-coated liposome aiming at obtaining an effective formulation able to ensure a prolonged and controlled release of NAC to the lung by inhalation. Empty liposomes [(DPPG/Chol/DPPG with different molar percentages of DPPG) (0, 1, 2.5, 5)] were prepared and coated with CH at different CH/Lipid ratio (0.5, 1, 1.5,2, 2.5, W/W) to reach optimum coating of CH. TEM and SEM indicated that morphology of CH-coated and -uncoated liposomes were spherical. FTIR analysis indicated attachment of CH on liposome surface. The drug release experiment in the simulated lung fluid showed that the CH-uncoated and -coated liposomes released 51% and 38% of NAC during 9 h, respectively. The results showed that coating of liposome with CH resulted in the prolonged release of NAC from CH-coated liposome. The results of flow cytometry indicated the effective uptake of CH-coated liposome compared with the CH-uncoated liposome in epithelial cells. In vivo experiment indicated good deposition and retention of CH-coated liposome in lung in comparison with CH-uncoated liposome. The results of the present study demonstrated that CH-coated liposome may represent a promising carrier for the delivery of NAC to the lungs by inhalation therapy.