The primary objective of the proposed research work is to extract and enrich the pure Andrographolide (AGL) by varying the polarity index and Hildebrand solubility parameter (δ) of a moderately polar solvent. Both parameters affect the solubility of AGL in different solvents and extraction methods. AGL was extracted from the whole plant of Andrographis paniculata. Continuous or Direct, Maceration and Soxhlet extraction method used for extraction. Based on the appearance of the crystal in the Direct Soxhlet Ethyl acetate method, their yield was further optimized by using a Randomized response surface (RSM), Quadratic model-based Box-Behnken design (BBD). The HPTLC performed the AGL extraction efficiency, purity, and quantification. Based on the obtained result, the pure Andrographolide crystal (yield 0.185 g/g) was obtained by Direct Soxhlet extraction. Ethyl acetate is used as a solvent. Rf exhibited in the TLC chromatogram was 0.28. FT-IR spectra exhibited characteristics peak similar to the standard AGL, and 1H-NMR, 13C NMR elucidated crystal structure. DEPT − 90/135 spectra depicted that extracted crystal was pure AGL. It is one of the novel approaches to isolating pure AGL crystal in a moderately polar solvent (Ethyl acetate) by elevating the Hildebrand solubility parameter despite using polar solvents. AGL crystal was obtained from Direct Soxhlet extraction by Ethyl acetate. It is a single-step and more economical method. It can be easily transformed into a pilot or industrial setup to extract Pure AGL.