Methane (CH4) is a potent greenhouse gas and ozone precursor. Quantifying methane emissions is critical for projecting and mitigating changes to climate and air quality. Here we present CH4 observations made from space combined with Earth‐based remote sensing column measurements. Results indicate the largest anomalous CH4 levels viewable from space over the conterminous U.S. are located at the Four Corners region in the Southwest U.S. Emissions exceeding inventory estimates, totaling 0.59 Tg CH4/yr [0.50–0.67; 2σ], are necessary to bring high‐resolution simulations and observations into agreement. This underestimated source approaches 10% of the EPA estimate of total U.S. CH4 emissions from natural gas. The persistence of this CH4 signal from 2003 onward indicates that the source is likely from established gas, coal, and coalbed methane mining and processing. This work demonstrates that space‐based observations can identify anomalous CH4 emission source regions and quantify their emissions with the use of a transport model.