AbstractApplication of the best available science to improve quantification of greenhouse gas (GHG) emissions at regional and national scales is key to climate action. Here, we present a two‐decade (2000–2019) GHG (CO2, CH4, and N2O) budget for Mexico derived from multiple products. Data from the National GHG Inventory, global observations, and the scientific literature were compared to identify knowledge gaps on GHG flux dynamics and discrepancies among estimates. Total mean annual GHG emissions were estimated at 695–910 TgCO2‐eq year−1 over these two decades, with 70% of the emissions attributable to CO2, 23% to CH4, and 5% to N2O (2% to other gases). When divided by sectors, we found agreement across emission estimates from various sources for fossil fuels, cattle, agriculture, and waste for all GHGs. However, considerable discrepancies were identified in the fluxes from terrestrial ecosystems. The disagreement was particularly large for the land CO2 sink, where net biome production estimations from the national inventory were double those from any other observational product. Extensive knowledge gaps exist, mainly related to aquatic systems (e.g., outgassing in rivers) and the lateral fluxes (e.g., wood trade). In addition, limited information is available on CH4 emissions from wetlands and soil CH4 consumption. We expect these results to guide future research to reduce estimation uncertainties and fill the information gaps across Mexico.