The inadequacies of the currently available treatment options for leishmaniasis, a highly prevalent but neglected tropical disease caused by protozoan parasites, urge the discovery and development of novel, safe, and efficacious antileishmanial drugs. In continuation of our work on N, N', N″-trisubstituted guanidines, which have shown promising results, we present in this study a series of new derivatives with further improved activity against the species Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis. This enhancement was achieved by replacing the benzoyl group as one of the three guanidine substituents of the starting structures with an acridinyl group, which consistently decreased the IC50 values against the promastigote form of L. (V.) braziliensis by a factor of 5.7-37. The three most active acridinylguanidines all showed submicromolar IC50 values against the promastigote forms of all three tested parasite species and a selectivity index >200 compared to RAW 264.7 macrophages. Similar results were obtained against L. (V.) braziliensis axenic and intramacrophage amastigotes, with ACRL-G5 showing an EC50 of 0.53 μM against both and a selectivity index of 347. ACRL-G5 was also shown to increase the levels of TNF-α and nitric oxide and to decrease the concentration of IL-10 in the supernatant of L. (V.) braziliensis-infected macrophages. All three tested acridinylguanidines strongly increased the membrane permeability of L. braziliensis promastigotes at concentrations above the IC50.