The study aimed to develop thiolated pluronic‐based self‐emulsifying drug delivery system (SNEDDS) targeted delivery of Rifampicin coated by arginine for enhanced drug loading, mucoadhesion, muco penetration, site‐specific delivery, stabilized delivery against intracellular mycobacterium tuberculosis (M. tb), decreased bacterial burden and production by intracellular targeting. Oleic oil, PEG 200 and Tween 80 are selected as oil, co‐surfactant and surfactant based on solubilizing capacity and pseudo ternary diagram region. Coating of thiolated polymer on SNEDDS with ligand arginine (Arg‐Th‐F407 SNEDDDS) decreased bacterial burden and production by intracellular targeting in macrophages. Formulation are evaluated through scanning electron microscope (SEM), EDAX analysis, diffraction laser scattering (DLS), Fourier transform infrared (FTIR) spectroscopy, and thermal analysis (DSC & TGA). Hydrodynamic diameter of thiolated polymeric SNEDDS (Th‐F407 SNEDDS) and Arg‐Th‐F407 SNEDDS is observed to be 148.4 and 188.5 nm with low PDI of 0.4 and 0.3, respectively. Invitro drug release study from Arg‐Th‐F407 SNEDDS indicates 80% sustained release in 72 h under controlled conditions. Arg‐Th‐F407 SNEDDDS shows excellent capability of killing M.tb strains in macrophages even at low dose as compared to traditional rifampicin (RIF) and is found biocompatible, non‐cytotoxic, and hemocompatible. Therefore, Arg‐Th‐F407 SNEDDDS of RIF proved ideal for targeting and treating M.tb strains within macrophages.