Purposes: The present study aimed to develop brimonidine tartrate loaded poly(lactic-co-glycolic acid) acid vitamin E-tocopheryl polyethylene glycol 1000 succinate (BRT-PLGA-TPGS) nanoparticles in thermosensitivein situ gel to improve mucoadhensive properties and drug holding capacity for the better management of glaucoma.Methods: Nanoparticles was optimized by means of Box-Behnken Design (BBD). The formulations were prepared using various concentration of PLGA (0.1-0.4% w/v) and TPGS (0.3-0.5% w/v). The analytical data of fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) depicted the drug excipients compatibility and confirmed the nanoparticles. Nanoparticles incorporated gel was evaluated for transcorneal permeability, gelation time, gelling temperature, and rheological studies. In addition, in vitro, transcorneal permeation drug release studies and intraocular pressure (IOP) for optimized gel was also performed. Biocompatibility of formulations was investigated in rabbit model.Results: The drug loaded nanoparticles exhibited 115.72 ± 4.18 nm, 0.190 ± 0.02, -11.80 ± 2.24 mV and 74.85 ± 6.54% of mean size, polydispersity index (PDI), zeta potential and entrapment efficiency (% EE), respectively. As compared to marketed eye drop, the sustained and continuous release BRT release from Poloxamer-based in situ gel was 85.31 ± 3.51% till 24 h. The transcorneal steady-state flux (136.32 μg cm^-2 h^-1) of optimized in situ gel was approximately 3.5 times higher than marketed formulation (38.60 μg cm^-2 h^-1) flux at 4 h. The optimized formulation produces 3 fold greater influences on percentage reduction of IOP (34.46 ± 4.21%) than the marketed formulation (12.24 ± 2.90%) till 8 h.Conclusion: The incorporation of optimized BRT-PLGA-TPGS nanoparticles into a thermosensitivein situ gel matrix to improve precorneal residence time without causing eye irritation and also serve the sustained release of BRT through cornea for effective management of glaucoma.