Coal fly ash (CFA) is an ideal source for the preparation of heterogeneous catalysts due to its abundant silicon and aluminum oxides, but its activity needs to be improved. In this study, a green and moderate approach for CFA activation was proposed, and a series of CFA-based catalysts were prepared for NO selective catalytic reduction (SCR). The results indicated that CFA could be well activated via mechanochemical activation with 3 h of milling duration in 1 mol/L of acetic acid, and 90% of NO removal was achieved over the CFA-based catalyst in 250 to 375 °C. Two activating mechanisms, i.e., the enhanced CFA fragmentation and the motivated Al dissolution, were revealed during the mechanochemical activation. The former facilitated the formation of mesopores and the exposure of Fe components in CFA fragments, which enhanced the capacity of oxygen storage over the as-activated catalyst. The latter motivated the formation of Si−OH groups, which promoted the migration of electrons and the dispersion of V species, thereby increasing the capacity of NH 3 adsorption over the as-obtained catalyst. Therefore, the performance of NO reduction was improved. The proposed activating approach could be a promising integration for CFA disposal and NO removal from inside coal-fired power plants.