Regulatory agencies prioritize the safety and effectiveness of pharmaceuticals. The focus here is to highlight the crucial need for control and oversight of Pretomanid (PMD), a synthetic nitroimidazooxazine utilized in treating multidrug-resistant tuberculosis. This study aims to develop a simple, sensitive, LCMS compatible, and environmentally friendly HPLC Stability Indicating Analytical Method following ICH Q1A (R2) and Q3 guidelines. The approach involves the application of Quality by Design (QbD) principles and adherence to green chemistry practices. A comprehensive risk assessment was conducted using cause-and-effect diagram and risk assessment tool. The QbD approach includes screening and optimization phases. Plackett-Burman design was performed for screening selected 11 primary parameters. Central composite design was used for optimisation of selected critical variables based on critical method parameters (CMPs) and Critical method attributes (CMAs). The method was optimised using Contour plot, 3D plot, ANOVA, Desirability value and Design space. Superior component separation was achieved through an isocratic elution using Kromasil C18 (250 × 4.6 mm; 5 μm) column, mobile phase composition of (50:50; v/v) ACN: 10 mM Ammonium Acetate pH 4.5 adjusted with Glacial Acetic acid and a flow rate of 0.9 mL/min having runtime of 30 mins. The stress studies revealed that the drug is highly sensitive to hydrolysis, oxidation, and photolytic conditions. Experimentation results demonstrated that acetonitrile served as the most suitable diluent. Additionally, the correlation coefficient (r2) exceeded 0.996, while the RSD values (n = 6) varied from 0.76 % to 1.93 % across the LOQ–150 % range. Specificity studies revealed no interference between peaks from impurities and known active analytes. Through stress studies, major degradation products were identified. The method's eco-friendliness was assessed using ComplexGAPI and AGREE, confirming its environmentally friendly nature.