The Ni-loaded cryptomelane-type manganese oxide octahedral molecular sieve (OMS-2) catalysts (xNi/OMS-2: x = 1, 3, 5, and 10 wt%) were prepared by a pre-incorporation method. Physicochemical properties of the as-synthesized materials were characterized by means of various techniques, and their catalytic activities for CO, ethyl acetate, and toluene oxidation were evaluated.The loading of Ni played an important role in improving physicochemical propertiesof OMS-2. Among all of the samples, 5Ni/OMS-2 exhibited the best catalytic activity, with the T90 being 155 °C for CO oxidation at a space velocity (SV) of 60,000 mL/(g·h), 225 °C for ethyl acetate oxidation at an SV of 240,000 mL/(g·h), and 300 °C for toluene oxidation at an SV of 240,000 mL/(g·h), which was due to its high Mn3+ content and Oads concentration, good low-temperature reducibility and lattice oxygen mobility, and strong interaction between the Ni species and the OMS-2 support. In addition, catalytic mechanisms of the oxidation of three pollutants over 5Ni/OMS-2 were also studied. The oxidation of CO, ethyl acetate, and toluene over the catalysts took place first via the activated adsorption, then intermediates formation, and finally complete conversion of the formed intermediates to CO2 and H2O.