Trypanosomatids are protozoan parasites responsible for leishmaniasis, Chagas disease and sleeping sickness. The design of new antitrypanosomatid drugs with trypanosomicidal and leishmanicidal activities is an effective perspective. The thiazolidinone ring is an important scaffold for several biological disorders. Herein, 4‐oxothiazolidine‐5‐acetic acids (1 a‐1 w) have been synthesized from respective thiosemicarbazone and maleic anhydride. Some of these 4‐oxothiazolidine‐5‐acetic acids were toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 1 e (IC50=10 μM), 1 u (IC50=8.94 μM), 1 g (IC50=5.65 μM) and 1 w (14.06 μM) showed the best anti‐T. cruzi activity for trypomastigote form, while 1 e, 1 u and 1 g showed SI higher than benznidazole (BZD). Similarly, against epimastigote the compound 1 q (IC50epi= 4.70 μM) has been found more selective and most active than benznidazole. However, evaluation against T. cruzi revealed that most of the active compounds have a low inhibition profile and weak leishmanicidal activity. In silico data suggests a good drug‐likeness profile, high chemical stability and demonstrate the use of these compounds in the designing of new anti‐T. cruzi and anti‐Leishmanial drugs.