Supercritical carbon dioxide (SC-CO2) extraction of xanthones from mangosteen pericarp was carried out at the following operational condition: pressure of 20, 25, and 30 MPa and temperature of 40, 50, and 60 °C. A total xanthone yield of 7.56% (w/w) was obtained at 30 MPa and 60 °C. A rapid and sensitive high performance liquid chromatography/electron spray ionization mass spectrometry (HPLC/ESI-MS) method was developed for the quantification of xanthones with mobile phase containing acetonitrile:methanol and a weak organic acid. The SC-CO2 operating conditions impacted enrichment of xanthones when compared to ethanol extract by Soxtec method. The structures of xanthones isolated were established on the basis of nuclear magnetic resonance (NMR) and mass spectroscopic studies.