Leishmaniases are neglected diseases with limited therapeutic options. Diffuse cutaneous leishmaniasis can occur in Brazil due to . This study details the antileishmanial activity and cytotoxicity of complexes of sodium usnate (SAU) with lanthanide ions ([LnL (HO)] (Ln = La(III), Nd(III), Gd(III), Tb(III), Eu(III) and Sm(III); L = SAU). All lanthanide complexes were highly active and more potent than SAU against promastigotes and intracellular amastigotes (Pro: IC < 1.50 μM; Ama: IC < 7.52 μM). EuL·3HO and NdL·3HO were the most selective and effective on intracellular amastigotes, with a selectivity index of approximately 7.0. In silico predictions showed no evidence of mutagenicity, tumorigenicity or irritation for all complexes. Treatment with EuL·3HO triggered NO release even at the lowest concentration, indicating NO production as a mechanism of action against the parasite. Incubating promastigotes with the lanthanide complexes, particularly with SmL·4HO and GdL·3HO, led to a change in the mitochondrial membrane potential, indicating the ability of these complexes to target this essential organelle. The same complexes caused cell death through cell membrane disruption, but their relationship with early or late apoptotic processes remains unclear. Thus, the inclusion of lanthanide ions in SAU improves selectivity with a promising mechanism of action targeting the mitochondria.