The present study was designed to synthesize some innovative multifunctional polymeric excipients for improved efficacy and site-specific delivery of antiLeishmanial drugs. Therefore, mannose anchored thiolated chitosan-graftedpolyethyleneimine (M-(CS-g-PEI)-TGA) polymeric excipient was synthesized and utilized for the development of first-line Meglumine Antimoniate (MA) antiLeishmanial drug nanoformulation to address the cellular bioavailability limitations. On the other hands, mannose anchored thiolated chitosan (M-CS-TGA) polymeric excipient was manufactured for the production of second-line Amphotericin B (AmB) anti-Leishmanial drug nanoformulation to reduce off-target adverse events by specific pathological organs reservoirs delivery. The newly synthesized M-(CS-g-PEI)-TGA polymeric excipient graft was evaluated for Trypanothione Reductase (TR) enzyme inhibition as a potential target. The observed hydrodynamic size of M-(CS-g-PEI)-TGA based MA nanoformulation and M-CS-TGA based AmB nanoformulation was found to be 287 ± 20 and 482 ± 17 respectively, with positive zeta-potential and low PDI. M- (CS-g-PEI)-TGA based MA nanoformulation showed the maximum macrophage internalization uptake of 61.47 ± 0.25 µg/106 cells. The flow cytometry analysis against Leishmania donovani infected macrophage model demonstrated 7.9- and 23-folds enhanced efficacy of M-(CS-g-PEI)-TGA based MA nanoformulation and M-CS-TGA based AmB nanoformulation as compared to MA and AmB, respectively. The results of in-vivo BALB/c mice visceral Leishmaniasis model for M-(CS-g-PEI)-TGA based MA nanoformulation displayed 5.22-fold decreased parasitic burden (p < 0.0001) compared to that of MA. For maximum selective targeting of the pathological organ while minimizing exposure to the organs prone to toxic effects, in vivo tissue distribution study, was conducted. M-CS-TGA based AmB nanoformulation showed a higher concentration of AmB (101 mg) in the liver as compared to the native AmB drug (43 mg). But in the case of the kidney, the M-CS-TGA based AmB nanoformulation revealed less concentration of AmB with respect to native AmB drug. Inorder to establish the safety profile of the AmB nanoformulation, the acute oral toxicity in female Swiss mice did not show any evident change in cellular morphology supporting the safety of M-CS-TGA due to renal clearance. The oral pharmacokinetic studies showed that M-(CS-g-PEI)-TGA based nanoformulation and M-CS-TGA based nanoformulation significantly enhanced bioavailability of MA and AmB respectively. The observed enhanced pharmacokinetic profile might be due to permeation enhancing potential of synthesized polymeric excipients. Based on these findings, incorporation of new multifunctional polymeric excipients for the development of macro phage targeted nano formulation seems to be a promising strategy to enhance the efficacy and safety of the anti-Leishmanial drug.