When exposed to depleted uranium (DU), the respiratory tract is the main route for DU to enter the body. At present, lung lavage is considered to be a method for removing DU from the lung. However, there is still room for improvement in the efficiency of lung lavage. In this work, a model of DU dust inhalation injury was established in beagle dogs so that chitosan-diethylenetriaminepentaacetic nanoparticles (CS-DTPA NP) could be synthesized. The purpose of this work was to evaluate the removal efficiency of CS-DTPA NP combined with lung lavage in dogs. Results showed that 7 d after DU exposure, the diethylenetriaminepentaacetic (DTPA) and CS-DTPA NP groups showed lower U content in kidney tissue compared with the normal saline (NS) group. In the left lung tissue (lavage fluid and recovery rate of lavage fluid), the U content in the CS-DTPA NP group was higher than in the NS and DTPA groups. In terms of blood levels, the CS-DPTA NP group increased over time at 1, 3 and 7 d of DU exposure without lavage; however, the U levels in the 3 and 7 d lavage groups were significantly lower than in the non-lavage groups. IL-1 in the lavage fluid of the CS-DPTA NP and CS NPs group were lower than in the NS group. In summary, after respiratory exposure to DU, early inhalation of CS-DPTA NP may block insoluble DU particles in the lung, and if combined with lung lavage, the clearance efficiency of DU from lung tissue improves. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Health Physics Society.