Chagas disease is a neglected tropical disease, endemic in Latin America and caused by the protozoan parasite Trypanosoma cruzi. Available treatments show low cure efficacy during the chronic phase of the disease and cause a series of side effects, reinforcing the need to develop new drugs against Chagas disease. In this work, we describe the optimization of a trypanocidal hit compound recently reported in phenotypic high‐throughput screening studies against Trypanosoma cruzi. A hit‐to‐lead process was initiated and a structure‐activity relationship against Trypanosoma cruzi was obtained after the synthesis and biological evaluation of 22 new benzenesulfonylpiperazine derivatives. From this structure‐activity relationship study, we identified three compounds with a promising predicted ADMET profile and potency comparable to the reference drug benznidazole, which are candidates for further development towards therapies for Chagas disease.