A broad suite of characteristics and events drive carbon cycling and greenhouse gas (GHG) emissions in lakes and reservoirs. Many of these occur at the watershed scale or involve activities that are connected via river networks, such as land cover/use or vegetation and streamflow alteration. Variations in inputs and characteristics create a challenge for determining representative conditions used in calculations of GHG footprints. Additionally, regulated lakes and human-created reservoirs throughout the world vary widely on spectrums of morphology, size, inputs, and climate/environmental settings, making it difficult to generalize GHG emissions phenomenon. Finally, some watersheds may experience major events such as wildfires that can drastically change expected carbon loading, processing, or emissions processes. We use a combination of remotely sensed data, national/global models of streamflow and climate, and large-scale monitoring campaigns to assess variability from seasonal to decadal scales for essential characteristics including lake characteristics (e.g., surface area, littoral area), land use/land cover, location and size of wetlands, inflow, and water quality characteristics. Variability is assessed in terms of autocorrelation, trends over time, and degree of change over epochs. We then compare estimates of GHG footprints using several models from literature to demonstrate how variability in lake and watershed characteristics relate to uncertainty of a reservoir’s GHG footprint. This provides important feedback for large-scale GHG accounting and estimating contributions of aquatic systems to global carbon and GHG processes.