The organic/inorganic hybrid CH3NH3PbI3 perovskite shows promising features in light harvesters, but its instability under humid environment seriously restricts its application. To improve the long-term stability, it is imperative to understand the degradation mechanism at the atomic level. Here, we apply the density functional theory (DFT)+U method to systematically investigate the effect of light and the chemical interaction between the orthorhombic CH3NH3PbI3 (ort-CH3NH3PbI3) and water and some key roles of water/light causing instability of ort-CH3NH3PbI3 are identified. First, we demonstrate that the identified U values (I: 8 eV, Pb: 9 eV) in the DFT+U approach together with spin-orbit coupling can well describe the electronic and basic chemical properties of ort-CH3NH3PbI3, which is a good balance between the accuracy and computational cost. Second, the photogenerated hole is revealed to thermodynamically promote the formation of surface and bulk iodine vacancies in ort-CH3NH3PbI3(100) system that may induce the hysteresis behavior in current-voltage (J-V) curves and aging of perovskite solar cells. More importantly, the formed defect of iodine vacancy would induce H2O to undergo irreversible dissociation. Third, on the perfect ort-CH3NH3PbI3(100) surface in the dark, H2O is found to be difficult to dissociate and incline to molecularly adsorb; in contrast, with a photogenerated electron involved, the dissociation of H2O molecule becomes favorable with a decreased barrier of 0.57 eV. H2O dissociation results in the formation of hydroxyl anion (OH-), which can strongly interact with CH3NH3 + and lead to the formation of CH3NH2, thereby accelerating the ort-CH3NH3PbI3 degradation. © 2018 American Chemical Society.