The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q fever, as it enhances the activity of the antibiotic against the causative bacterium Coxiella burnetii residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could also be the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activities of combinations of CQ with the standard drugs paromomycin (PM), miltefosine, and amphotericin B against Leishmania major and Leishmania mexicana In 72-h intracellular antileishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced 50% effective concentrations (EC50s) by over 5-fold against L. major and against normally insensitive L. mexicana parasites. In murine models of L. major and L. mexicana CL, daily coadministration of 50 mg/kg of body weight PM and 25 mg/kg CQ for 10 days resulted in a significant reduction in lesion size but not in parasite load compared to those for mice given the same doses of PM alone. Overall, our data indicate that PM-CQ combination therapy is unlikely to be a potential candidate for further preclinical development.