The WRF/Chem v3.7 is applied to 2001–2010 over the continental U.S. using the National Emission Inventory (NEI). This study will provide the baseline simulation for a future work to investigate the impacts of both climate and emission changes on the future regional air quality and human health. This paper focuses on the current year simulation design, comprehensive model evaluation, and sensitivity simulations that demonstrate the impacts of different reinitialization setup, cloud physical schemes, and emission inventories on the model predictions. Nine one-month sensitivity simulations by using different reinitialization setup and cloud microphysics and cumulus parameterizations are first conducted to provide the optimal model configurations. The model performance in predicting the regional meteorology and air quality on a decadal scale is further evaluated against available surface, satellite, and reanalysis data. The decadal WRF/Chem simulation by using NEI emissions (referred to as simulation NEI) performs well for major meteorological variables such as T2, RH2, WS10, and precipitation and shows good performance for major radiation variables such as SWDOWN, OLR, and SWCF. Large model biases still exist for cloud variables due to limitations of cloud dynamics/thermodynamics treatments and uncertainties associated with satellite retrievals. The simulation NEI also predicts O3 and PM2.5 well in terms of spatiotemporal distribution. Compared to a previous study using the Representative Concentration Pathway (RCP8.5) emissions, the simulation NEI performs better for most of variables, especially for precipitation and cloud radiative forcing due to better representation of cloud processes and also for O3 and PM2.5 in terms of spatiotemporal variations due to more accurate emission inventory. The evaluation results in this work are within the range or better than other previous studies using the WRF/Chem model and lay the foundation for more realistic projection of future climate and air quality in the future work.