Airborne measurements of methane emissions from oil and gas infrastructure were completed over two regions of Alberta, Canada. These top-down measurements were directly compared with region-specific bottom-up inventories that utilized current industry-reported flaring and venting volumes (reported data) and quantitative estimates of unreported venting and fugitive sources. For the 50 × 50 km measurement region near Red Deer, characterized by natural gas and light oil production, measured methane fluxes were more than 17 times greater than that derived from directly reported data but consistent with our region-specific bottom-up inventory-based estimate. For the 60 × 60 km measurement region near Lloydminster, characterized by significant cold heavy oil production with sand (CHOPS), airborne measured methane fluxes were five times greater than directly reported emissions from venting and flaring and four times greater than our region-specific bottom up inventory-based estimate. Extended across Alberta, our results suggest that reported venting emissions in Alberta should be 2.5 ± 0.5 times higher, and total methane emissions from the upstream oil and gas sector (excluding mined oil sands) are likely at least 25–50% greater than current government estimates. Successful mitigation efforts in the Red Deer region will need to focus on the >90% of methane emissions currently unmeasured or unreported.