Sleeping sickness and leishmaniasis are neglected tropical diseases that threaten millions of people. The currently available therapies present several limitations, including high toxicity, lack of efficacy, and emerging drug resistance, prompting a search for novel therapeutic agents. In this work, we designed, synthesized, and <i>in vitro</i> evaluated the activity of new pyrimido[5,4-<i>d</i>]pyrimidines against <i>Trypanosoma brucei</i> and <i>Leishmania infantum</i> (promastigote and amastigote forms). The cytotoxicity of the compounds against the THP1 cell line was also assessed. Most tested compounds presented low micromolar activity against <i>T. brucei</i> with IC<sub>50</sub> values in the range between 0.9 and 13.4 μM, and one compound also showed activity against <i>L. infantum</i> (IC<sub>50</sub> = 3.13 μM). Several molecules presented a selectivity index higher than 10. The most active compound against booth parasites is derivative <b>4c</b>, with IC<sub>50</sub> = 0.94 μM (SI > 107) against <i>T. brucei</i> and IC<sub>50</sub> = 3.13 μM (SI > 32) against <i>L. infantum.</i> This data enabled the identification of a new promising molecular scaffold for developing a novel class of antitrypanosomal and antileishmanial agents.