In this study, we fabricated PCL-nanoparticles by encapsulating dual drugs as amphotericin B and doxorubicin via double-emulsion solvent evaporation method also incorporated with ligand-lectin for targeting the infested macrophage cells and prove importance against VL. Different independent processing parameters were assessed systematically to enhance the incorporation of the dual agents with different properties (AmB and DOX, hydrophobic & hydrophilic molecule, respectively) into PCL-NPs and control particle size. Approaches investigated for the enhancement of drug entrapment efficiencies and smaller particle size included the influence of the drug content, polymer content, sonication time etc. The mean particle size and zeta potential of PCL-NPs were 236.7 ± 0.04 nm in diameter and -9.11 ± 3.46 mV, respectively. The entrapment efficiencies of AmB and DOX were 82.1 ± 1.39 and 75.20 ± 0.14 %, respectively. Antileishmanial activities of the formulations and various combination approaches were assessed using macrophage-specific ligand-lectin. The prepared plain and lectin coated PCL-NPs based systems showed remarkable potential for passive and active intra macrophage targeting, respectively and the approach could be a successful alternative to the currently available drug regimens against VL. Multidrug resistance can be improved by combination delivery of encapsulated anti VL drugs. Thus, the co-encapsulation of AmB and DOX should reduce side effects of both drugs while increasing efficacy.