Natural and synthetic coumarins have been described as prototypes of new drug candidates against Chagas’ disease. During a typical screening with new compounds, we observed the potential of a new synthetic nitrobenzoylcoumarin (1) as trypanocidal against Trypanosoma cruzi epimastigotas. Then, we decided to prepare and evaluate a set of analogues from 1 to check the major structural requirements for trypanocidal activity. The structural variations were conducted in six different sites on the original compound and the best derivative (3) presented activity (IC₅₀ 28 ± 3 μM) similar to that of benznidazole (IC₅₀ 25 ± 10 μM). The enhancement of trypanocidal activity was conditioned to a change in the side chain at C6 (allyl to n‐propyl group) and the preservation of coumarin nucleus and the nitrobenzoyl group at C3. Exposure of 3 to H9C2 cells showed low toxicity (CC₅₀ > 200 μM) and its activity on T. cruzi amastigotes (IC₅₀ 13 ± 0.3 μM) encouraged us to perform an evaluation of its potential when given orally to mice infected with trypomastigote forms. Derivative 3 was able to reduce parasitemia when compared to the group of untreated animals. Taken together, these results show the potential therapeutic application of the synthetic coumarins.