<p>This study presents the development and validation of a robust, stability-indicating instrumental thin-layer chromatography (TLC) method for the quantification of itraconazole in tablet dosage form using a quality by design (QbD) approach. Central composite design (CCD) was employed to optimize key chromatographic parameters such as saturation time, solvent front, and mobile phase ratio (toluene–ethyl acetate–formic acid, 60:40:0.5, <i>V/V</i>). The method demonstrated excellent linearity over the range of 1000–5000&#xa0;ng/band with a correlation coefficient (<i>r</i>²) of 0.9998. Precision studies showed percentage relative standard deviation (%RSD) values below 2%, and accuracy was confirmed with a recovery range of 99.95–100.05%. The method was validated as per the International Council for Harmonisation (ICH) guidelines and showed robustness under minor variations. Forced degradation studies confirmed the method’s stability-indicating nature with distinct degradation peaks observed under acidic, alkaline, oxidative, thermal, and photolytic stress. The environmental impact of the method was assessed using the Blue Applicability Grade Index (BAGI), scoring 65, and the Green Analytical Procedure Index (GAPI), confirming its ecofriendliness. This work is the first to report a CCD-optimized, green, instrumental TLC method for itraconazole, making it a scientifically valuable tool for routine quality control in pharmaceutical industries that aligns with green chemistry and regulatory expectations.</p> Graphical Abstract <p></p>