The major goal of the current research was to develop and evaluate the therapeutic potential of anti-tubercular drugs (ATDs) loaded natural polysaccharide comprising of galacto mannan subunit in experimental tuberculosis (TB). Experimental formulations were prepared by ionotropic gelation technique followed by spray drying. Morphological analysis suggested that optimized nanoparticles were found to be discrete and spherical in nature with a particle size distribution range from 230 ± 4.5 nm to 310 ± 6.2 nm. The in-vitro drug release behavior indicated the biphasic pattern comprising of initial burst followed by a sustained release pattern. Guar gum coated chitosan nanoparticles (CGNPs) among the leading formulation exhibited the highest cell uptake potential confirmed by FACS analysis. Challenge study also supports the in-vivo bio-distribution illustrated by the significant reduction in CFU count in experimental TB in mice. Histopathology study demonstrated that none of the treated group shows any evidence of lung tissue abnormality. Hence, the study marked the fact that CGNPs could be a promising carrier for selective delivery of ATDs to alveolar macrophages for efficient management of TB with the interception of minimal side effects.