Plumbagin, a naphthoquinone that is found in the root system of the Plumbago Indica plant, possesses a variety of therapeutic benefits. Box-Behnken Design (BBD) was utilised to optimise the procedure variables employed in the plumbagin extraction process from Plumbago Indica roots. Quality by Design (QbD), and more specifically BBD, was utilized to optimize the extraction parameters, which included extraction duration, the ratio of solvent to drug, and extraction temperature. The quantity of plumbagin found in several different extracts was determined using high-performance, thin-layer chromatography (HPTLC). In conjunction with that, the DPPH method was utilized to assess the antioxidant capabilities of several Plumbago Indica extract solutions. The optimal extraction temperature for plumbagin was found to be 52.50 °C, the ratio of the solvent to the drug was found to be 22.50 ml per gram, and the extraction time was found to be 30 min when using BBD. Under these conditions, the plumbagin yield turned out to be 1.981 mg/g. It has been proven that the extract of methanolic solvent possesses DPPH activity, as evidenced by inhibition of 87.11%. It was found that methanol was the most effective solvent for extraction, and the ultrasound-assisted extraction method was the most effective of all the thermal and non-thermal extraction strategies utilized. The current work emphasizes the utilization of QbD in the extraction of potentially active compounds, which helps reduce the amount of time and effort necessary for optimization.