Xanthones are an important class of secondary metabolites present in mangosteen fruit pericarp. Herein we have used supercritical fluid technology to extract the active constituents from mangosteen pericarp. Ethanol was added (5% w/w) as a co-solvent to increase the polarity of the CO2, thus favouring the extraction of xanthones. The maximum extraction yield of 15 wt.% was achieved at a pressure of 280 bar, temperature of 50 °C and a time of 8 h, while without co-solvent the yield was 7.5 wt.%. Conditions for antioxidant activity as measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay was 280 bar at 50 °C and 5 h. Box–Behnken design was used to study the efficiency of extraction pressure (180, 280, and 380 bar), temperature (40, 50, and 60 °C) and time (2–8 h) on the total extraction yields and their radical scavenging activity. Experimental results of the total extract yield and radical scavenging activity were close to the predicted values calculated from the polynomial response surface models equations (R2 = 0.99 and 0.98).