To understand the molecular-level reaction mechanism and crucial activity-limiting factors of the NH3-SCR process catalyzed by MnO2-based oxide to eliminate NO (4NH3 + 4NO + O2 →4N2 + 6H2O) at middle-low temperature, a systematic computational investigation is performed on β-MnO2(110) by first-principles calculations together with microkinetic analysis. Herein, the favored reaction pathways are unveiled. (i) NH3 tends to adsorb at the unsaturated Lewis acid Mn5c site on MnO2(110) and then partially dissociates into NH2∗ (assisted by the surface lattice Obri) at the steady state, triggering the subsequent reactions. (ii) Interestingly, NO, either in the gas phase or at the adsorbed state, can readily react with NH2∗ to give the key intermediate NH2NO, with the former (i.e., the Eley-Rideal pathway) being slightly more kinetically preferred. (iii) NH2NO conversion is identified to proceed easily to N2 through the dehydrogenation/hydrogenation processes NH2NO → NHNO → NHNOH → N2 + H2O. (iv) The removal of the accumulated surface H into H2O, assisted by O2, is relatively difficult, which preferentially occurs via the Mars-van Krevelen mechanism. Quantitatively, a kinetic analysis is conducted to deal with such a complex reaction network, revealing that the rate-limiting steps are NH2∗ + NO(g) → NH2NO∗ and ObriH + O2# →OOH# + Obri. Moreover, a sensitivity analysis shows that the adsorption strengths of H on Obri and O2 in the Obri vacancy (Ovac) are two main activity-determining factors for the overall NH3-SCR on MnO2(110); notably, it is further found that the Ovac formation energy correlates well with both factors and can thus serve as a unified activity descriptor. In addition, the effects of catalyst surface environment under the reaction conditions on the NH3-SCR activity and selectivity are discussed. In comparison with the pristine state of MnO2(110), both the overall activity and N2 selectivity (versus N2O) would be interestingly enhanced when it arrives at the kinetically steady state that the surface Obri are largely covered by H. These results could provide a consolidated theoretical basis for understanding and optimizing MnO2 catalysts for the NH3-SCR process. © 2018 American Chemical Society.