Justicia gendarussa Burm.f contains polyphenol, which has pharmacological activity. Therefore, this study aims to show the potential of antioxidant compounds in J. gendarussa. The extraction method used was an experimental design that maximized phenolic recovery with the highest antioxidant activity from the leaves of this plant. Furthermore, a simplex-centroid design was used to evaluate the various extractor solvents (water, ethanol, and hexane) and their binary or ternary mixtures, while UPLC-MS/MS analysis was used to identify bioactive compounds. The total phenol (TPC) and flavonoid content (TFC) of the optimized extracts were determined using Follin-Ciocalteu and colorimetric methods, as well as their antioxidant activity were determined using the 2,2-diphenyl-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. The results was optimized to a value of 0.844 using water-hexane solvents with a predicted TPC, TFC, DPPH, and FRAP of 112.076 mg GAE/g, 34.926 mg QE/g, 45.477 µmol TE/g, and 353.611 µmol TE/g, respectively. Additionally, the UPLC-MS/MS analysis showed 62 compounds such as phenolics, isoflavonoids, alkaloids, terpenoids, alcohols, and other groups of components. This study shows the potential of antioxidant compounds J. gendarussa. Keywords: Extraction optimization, Justicia gendarussa Burm.f, Simplex centroid design, Polyphenols, Antioxidant