Despite the inherent stability of glycosidic linkages in nucleic acids that connect the nucleobases to sugar-phosphate backbones, cleavage of these bonds is often essential for organism survival. The current study uses DFT (B3LYP) to provide a fundamental understanding of the hydrolytic deglycosylation of the natural RNA nucleosides (A, C, G, and U), offers a comparison to DNA hydrolysis, and examines the effects of acid, base, or simultaneous acid-base catalysis on RNA deglycosylation. By initially examining HCOO-center dot center dot center dot-H2O mediated deglycosylation, the barriers for RNA hydrolysis were determined to be 30-38 kJ mol(-1) higher than the corresponding DNA barriers, indicating that the 2'-OH group stabilizes the glycosidic bond. Although the presence of HCOO- as the base (i.e., to activate the water nucleophile) reduces the barrier for uncatalyzed RNA hydrolysis (i.e., unactivated H2O nucleophile) by similar to 45-20 kJ mol(-1), the extreme of base catalysis as modeled using a fully deprotonated water molecule (i.e., OW nucleophile) decreases the uncatalyzed barriers by up to 65 kJ mol(-1). Acid catalysis was subsequently examined by selectively protonating the hydrogen-bond acceptor sites of the RNA nucleobases, which results in an up to similar to 80 kJ mol(-1) barrier reduction relative to the corresponding uncatalyzecl pathway. Interestingly, the nudeobase proton acceptor sites that result in the greatest barrier reductions match sites typically targeted in enzyme-catalyzed reactions. Nevertheless, simultaneous acid and base catalysis is the most beneficial way to enhance the reactivity of the glycosidic bonds in RNA, with the individual effects of each catalytic approach being weakened, additive, or synergistic depending on the strength of the base (i.e., degree of water nucleophile activation), the nudeobase, and the hydrogen-bonding acceptor site on the nucleobase. Together, the current contribution provides a greater understanding of the reactivity of the glycosidic bond in natural RNA nucleosides, and has fundamental implications for the function of RNA-targeting enzymes.