The present study is aimed to design and develop linezolid loaded PLGA nanoparticles (LZ NPs) for treatment of pulmonary tuberculosis. The objective was to prepare LZ NPs with a mean particle size below 300 nm and having Mass Median Aerodynamic Diameter (MMAD) less than 5 μm and sustain the drug release up to 120 h. The LZ NPs were prepared by modified emulsion solvent evaporation method using high-speed homogenization, sonication and subsequent lyophilization. Preliminary studies revealed that dimethyl sulphoxide was a suitable organic phase while α – phosphatidylcholine and PVP S 630 D were the suitable stabilizers for stabilizing the nanoparticles. A 3² full factorial design revealed that both process variables namely homogenization time and homogenization speed had a significant effect (p < 0.05) on all the selected dependent variables. Further, the optimum formulation had the mean particle size 45.8 nm, entrapment efficiency up to 85.33%, MMAD of 3.38 μm and sustained release up to 120 h in simulated lung fluid. Further, pharmacokinetic and pharmacodynamic studies can be conducted to evaluate the efficacy of in-house formulation on Mycobacterium tuberculosis-infected experimental animals.