Response surface methodology (RSM) was employed to optimize the extraction of herbal plant of Annona muricata L. using Box-Behnken Design (BBD). The Box-Behnken Design (BBD) with three factors and two responses (yield and total solid content) was implemented. The processing parameters of A. muricata leaves by soxhlet extraction were solvent to raw material ratio, ethanol concentration, and duration of extraction using soxhlet extractor. The presence of acetogenins compounds was screened by High Performance Liquid Chromatography. Optimum condition with the solvent to raw material ratio (1:5.92), ethanol concentration (1.67 %), and duration of extraction (6.84 hours) was obtained and further analyzed with antioxidant tests. Analyses showed the A. muricata leaves contained high total phenolic and flavonoid contents which corresponding to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity test. The DPPH result showed that the extract has the highest percentage of scavenging activity with the inhibitory concentration (IC50) value of leaves is 0.243 mg/mL + 0.001 nearly comparable to butylated hydroxyanisole (BHA) and ascorbic acid (Vit. C), which indicated that the leaves also have higher free radical scavenging activity compared to these commercial standards. Besides, the presence of primary; polysacharide (21.85 % + 0.001), protein (19.59 % + 0.000), glycosaponin (18.87 % + 0.001) and secondary; phenolic (47.26 mg GAE/1g + 0.001), flavonoid (22.12 mg CE/1g + 0.001) metabolites in A. muricata leaves suggested that the leaves contained strong antioxidant properties that are believed can act as anticancer agent for the body.