The catalytic combustion of methane at a low temperature is becoming increasingly key to controlling unburned CH4emissions from natural gas vehicles and power plants, although the low activity of benchmark platinum-group-metal catalysts hinders its broad application. Based on automated reaction route mapping, we explore main-group elements catalysts containing Si and Al for low-temperature CH4combustion with ozone. Computational screening of the active site predicts that strong Brønsted acid sites are promising for methane combustion. We experimentally demonstrate that catalysts containing strong Bronsted acid sites exhibit improved CH4conversion at 250 °C, correlating with the theoretical predictions. The main-group catalyst (proton-type beta zeolite) delivered a reaction rate that is 442 times higher than that of a benchmark catalyst (5 wt% Pd-loaded Al2O3) at 190 °C and exhibits higher tolerance to steam and SO2. Our strategy demonstrates the rational design of earth-abundant catalysts based on automated reaction route mapping.