Leishmaniasis are caused by protozoa of the genus Leishmania and affect millions of people worldwide. They are considered neglected diseases that primarily impact individuals in tropical and subtropical regions. The drugs currently available for treating this infection have limitations, such as high toxicity, adverse reactions, and a long therapeutic intervention period. Numerous studies, using various experimental models, have sought to develop more effective and less toxic chemotherapeutic agents against these protozoa. In this context, the present study aimed to evaluate the antileishmanial activity of two new dichalcogenides, LQ64 and LQ62, as well as their possible mechanism of action in promastigote forms of Leishmania amazonensis. Both substances, LQ64 and LQ62, exhibited activity against promastigote (IC50 = 2.35 and 12.59 µM, respectively), and amastigote forms (IC50 = 3.50 and 6.58 µM, respectively). Furthermore, the substances revealed selectivity for the parasite when analyzing their cytotoxicity in J774A‐1 macrophages. Moreover, electron microscopy analysis and mechanisms of action assays investigated in promastigote forms with both substances showed mitochondrial depolarization. This phenomenon possibly promoted changes in intracellular ATP levels, resulting in increased reactive species and lipid peroxidation, leading the parasites to oxidative stress. Additionally, the treatments induced changes in plasma membrane integrity, lipid body accumulation, alterations in the cell cycle, and phosphatidylserine externalization. Thus, the results indicate that LQ64 and LQ62 may induce characteristic changes in the protozoan suggestive of apoptosis cell death.