The potential of PLGA-nanoparticles as a carrier of amphotericin B and doxorubicin against visceral leishmaniasis was evaluated by macrophage-mediated drug targeting approach. PLGA-nanoparticles were modified by coating them with macrophage-specific ligand-lectin. Prior to in-vitro studies, characterization studies were carried out systematically include particle size, surface morphology, percent drug entrapment and percent drug release. In vitro studies were carried out in J774.1 in order to evaluate the effective endocytotic uptake of nanoparticles by macrophages. The antileishmanial activity of PLGA-nanoparticles and lectin-PLGA-nanoparticles was tested in-vitro in leishmania donovani infected macrophage-amastigote system (J774A.1 cells), which showed higher efficacy of lectin grafted PLGA-nanoparticles over plain PLGA-nanoparticles. The prepared plain and lectin grafted PLGA-Nanoparticles based systems showed excellent potential for passive and active intra-macrophage targeting, respectively and the approach could be an effective alternative to the currently available drug regimens against VL.