The high drug-carrying capacity and biocompatibility of chitosan (CS), a versatile biomacromolecule, have received special attention in recent years. This study focused on CS containing meglumine antimoniate (MA) for treating leishmaniasis, which was coated onto a silver/polyurethane (Ag.MA.CS/PUF). The newly synthesized nanocomposite was characterized using Fourier transform infrared spectroscopy (FTIR), inductively coupled plasma (ICP), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) surface area analysis, field emission scanning electron microscope/energy dispersive spectroscopy (FESEM/EDS), and transmission electron microscopy (TEM). To confirm the in vivo results, we administered the Ag.MA.CS/PUF nanocomposite topically to skin lesions caused by L. major (MRHO/IR/75/ER) in 56 inbred BALB/c mice in intervention (n = 42) and control (n = 14) groups, once daily for four weeks. Skin lesion sizes and amastigote counts were measured before treatment and four weeks post-treatment. At these intervals, the average size of skin lesions in the Ag.MA.CS/PUF group decreased by 28 %, from 3.02 ± 0.98 to 2.17 ± 0.33 mm