The high-pressure behavior of scandium oxide (Sc2O3) has been investigated by angle-dispersive synchrotron powder X-ray diffraction and Raman spectroscopy techniques in a diamond anvil cell up to 46.2 and 42 GPa, respectively. An irreversible structural transformation of Sc2O3 from the cubic phase to a monoclinic high-pressure phase was observed at 36 GPa. Subsequent ab initio calculations for Sc2O3 predicted the phase transition from the cubic to monoclinic phase but at a much lower pressure. The same calculations predicted a second phase transition at 77 GPa from the monoclinic to hexagonal phase.