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Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in <i>Leishmania</i> spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of <i>Leishmania major</i>, <i>L. amazonensis</i>, and <i>L. infantum</i>, as well as primary mouse macrophages infected with <i>L. major</i>. The novel inhibitor CPE2 emerged as the most active of a group of compounds against <i>Leishmania</i>, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, <i>L. major</i> promastigotes treated with CPE2 showed significant lower expression levels of several genes (<i>α-tubulin</i>, <i>Cyclin CYCA</i>, and <i>Yip1</i>) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.