In the present work 8-hydroxyquinoline-derived hydrazones were obtained, namely 2-formyl-8-hydroxyquinoline-4-nitroimidazolhydrazone (H2Q4NO₂Im) (H₂La, 1) and 2-formyl-8-hydroxyquinoline-4-nitrobenzenehydrazone (H2Q4NO₂Ph·H₂O) (H₂Lb, 2), as well as their antimony(III) [Sb(L)Cl₂] (3, 4) and bismuth(III) [Bi(L)Cl₂] (5, 6) complexes. The cytotoxic concentration range of the compounds was first determined in non-infected human and mouse cells. Furthermore, their antiparasitic activity against Trypanosoma cruzi, the causative agent of Chagas disease, was evaluated. While H₂Lb (2) was inactive, H₂La (1) and complexes 3–6 inhibited T. cruzi trypomastigotes with EC₅₀ values ranging from 0.06 to 30.05 μM. Complex 3 proved to be as potent as the reference drug benznidazole whereas complexes 4–6 were more potent than benznidazole as antiparasitic agents. The antimony(III) (4, EC₅₀ = 0.33 μM) and bismuth(III) (6, EC₅₀ = 0.06 μM) complexes presented the highest activities against the extracellular parasites. As expected, complexes 4 and 6 also exhibited the highest anti-T. cruzi activity against the amastigote form, with EC₅₀ values of 3.05 and 2.31 μM, respectively. Investigation of the mode of action of complex 6 on trypomastigotes suggested the occurrence of cell death by necrosis.