Ecosystem function (particularly CO2 fluxes and the subsequent atmospheric transport), synoptic‐scale weather (e.g., midlatitude cyclones), and interactions between ecosystems and the atmosphere can be investigated using a weather‐biosphere‐online‐coupled model. The Vegetation Photosynthesis and Respiration Model (VPRM) was coupled with the Weather Research and Forecasting (WRF) model in 2008 to simulate “weather‐aware” biospheric CO2 fluxes and subsequent transport and dispersion. The ability of the coupled WRF‐VPRM modeling system to simulate the CO2 structures within midlatitude cyclones, however, has not been evaluated due to the lack of data within these weather systems. In this study, VPRM parameters previously calibrated off‐line using eddy covariance tower data over North America are implemented into WRF‐VPRM. The updated WRF‐VPRM is then used to simulate spatiotemporal variations of CO2 over the contiguous United States at a horizontal grid spacing of 12 km for 2016 using an optimized downscaling configuration. The downscaled fields are evaluated using remotely sensed data from the Orbiting Carbon Observatory‐2, Total Carbon Column Observing Network, and in situ aircraft measurements from Atmospheric Carbon and Transport‐America missions. Evaluations show that WRF‐VPRM captures the monthly variation of column‐averaged CO2 concentrations (XCO2) and episodic variations associated with frontal passages. The downscaling also successfully captures the horizontal CO2 gradients across fronts and vertical CO2 contrast between the boundary layer and the free troposphere. WRF‐VPRM modeling results indicate that from May to September, biogenic fluxes dominate variability in XCO2 over most of the contiguous United States, except over a few metropolitan areas such as Los Angeles.