Mg can store up to similar to 7 wt.% hydrogen and has great potential as light-weight and low cost hydrogen storage materials. However hydrogen sorption in Mg typically requires similar to 573 K, whereas the target operation temperature of fuel cells in automobiles is similar to 373 K or less. Here we demonstrate that stress-induced orthorhombic Mg hydride (O-MgH2) is thermodynamically destabilized at similar to 373 K or lower. Such drastic destabilization arises from large tensile stress in single layer O-MgH2 bonded to rigid substrate, or compressive stress due to large volume change incompatibility in Mg/Nb multilayers. Hydrogen (H-2) desorption occurred at room temperature in O-MgH2 10 nm/O-NbH 10 nm multilayers. Ab initio calculations show that constraints imposed by the thin-film environment can significantly reduce hydride formation enthalpy, verifying the experimental observations. These studies provide key insight on the mechanisms that can significantly destabilize Mg hydride and other type of metal hydrides. Copyright (C) 2013, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.