Simulating the magnitude and variability of terrestrial methane sources and sinks poses a challenge to ecosystem models because the biophysical and biogeochemical processes that lead to methane emissions from terrestrial and freshwater ecosystems are, by their nature, episodic and spatially disjunct. As a consequence, model predictions of regional methane emissions based on field campaigns from short eddy covariance towers or static chambers have large uncertainties, because measurements focused on a particular known source of methane emission will be biased compared to regional estimates with regards to magnitude, spatial scale, or frequency of these emissions. Given the relatively large importance of predicting future terrestrial methane fluxes for constraining future atmospheric methane growth rates, a clear need exists to reduce spatiotemporal uncertainties. In 2010, an Ameriflux tower (US-PFa) near Park Falls, WI, USA, was instrumented with closed-path methane flux measurements at 122 m above ground in a mixed wetland–upland landscape representative of the Great Lakes region. Two years of flux observations revealed an average annual methane (CH4) efflux of 785 ± 75 mg CCH4 m−2 yr−1, compared to a mean CO2 sink of −80 g CCO2 m−2 yr−1, a ratio of 1% in magnitude on a mole basis. Interannual variability in methane flux was 30% of the mean flux and driven by suppression of methane emissions during dry conditions in late summer 2012. Though relatively small, the magnitude of the methane source from the very tall tower measurements was mostly within the range previously measured using static chambers at nearby wetlands, but larger than a simple scaling of those fluxes to the tower footprint. Seasonal patterns in methane fluxes were similar to those simulated in the Dynamic Land Ecosystem Model (DLEM), but magnitude depends on model parameterization and input data, especially regarding wetland extent. The model was unable to simulate short-term (sub-weekly) variability. Temperature was found to be a stronger driver of regional CH4 flux than moisture availability or net ecosystem production at the daily to monthly scale. Taken together, these results emphasize the multi-timescale dependence of drivers of regional methane flux and the importance of long, continuous time series for their characterization.