A series of Ag nanoparticles (NPs) supported on three-dimensionally ordered macroporous (3DOM) La0.6Sr0.4MnO3 (yAg/3DOM La0.6Sr0.4MnO3; y = 0, 1.57, 3.63, and 5.71 wt %) were successfully prepared with high surface areas (38.2–42.7 m2/g) by a facile novel reduction method using poly methacrylate colloidal crystal as template in a dimethoxytetraethylene glycol (DMOTEG) solution. Physicochemical properties of these materials were characterized by means of numerous techniques, and their catalytic activities were evaluated for the combustion of methane. It is shown that the yAg/3DOM La0.6Sr0.4MnO3 materials possessed unique nanovoid-like 3DOM architectures, and the Ag NPs were well dispersed on the inner walls of macropores. Among the La1–xSrxMnO3 (x = 0.2, 0.4, 0.6, 0.8) and yAg/3DOM La0.6Sr0.4MnO3 (y = 0, 1.57, 3.63, and 5.71 wt %) samples, 3.63 wt % Ag/3DOM La0.6Sr0.4MnO3 performed the best, giving T10%, T50%, and T90% (temperatures corresponding to methane conversion =10, 50, and 90%) of 361, 454, and 524 °C, respectively, and the highest turnover frequency (TOFAg) value of 1.86 × 10–5 (mol/molAg s) at 300 °C. The apparent activation energies (39.1–37.5 kJ/mol) of the yAg/3DOM La0.6Sr0.4MnO3 samples were much lower than that (91.4 kJ/mol) of the bulk La0.6Sr0.4MnO3 sample. The effects of water vapor and sulfur dioxide on the catalytic activity of the 3.63 wt % Ag/3DOM La0.6Sr0.4MnO3 sample were also examined. It is concluded that its super catalytic activity was associated with its high oxygen adspecies concentration, good low-temperature reducibility, large surface area, and strong interaction between Ag and La0.6Sr0.4MnO3 as well as the unique nanovoid-walled 3DOM structure.