Drugs for treating Leishmaniasis, a parasitic tropical orphan disease, currently have several limitations on their use, which topical treatments could alleviate. Topical treatment requires penetration of drugs deep into the skin, which is aided by encapsulation within ultradeformable liposomes. Penetrability depends on the flexibility of the lipid membrane, which may be affected by the drugs. We have studied the biophysical effects of four anti-Leishmania drugs (miltefosine (Milt), amphotericin B (AmpB), indole (Ind), and imiquimod (Imiq)) on a soy phosphatidylcholine/sodium cholate membrane. Using diffuse X-ray scattering techniques, we determined bending modulus ( KC) and chain order parameter ( SX-ray) of the membrane at several drug concentrations. Form factor scattering data allowed construction of electron density profiles, which yielded bilayer thickness and area per lipid. Results show that AmpB had the largest effect on KC and SX-ray, causing the bilayer to lose integrity at high concentrations. Imiq and Ind induced slight membrane stiffening, whereas Milt had little effect. Imiq also notably decreased chain order at high concentrations. These results will aid in the design of new topical treatments, where Milt, Ind, and Imiq could be used at any concentration without affecting liposome integrity or physical properties, whereas AmpB should not be used at high concentrations.