This work assessed the impact of aerosol-cloud-radiation (ACR) interactions on U.S. regional ozone and PM2.5 using the NASA Unified Weather Research and Forecasting modeling system. A series of three-month simulations have been carried out for the year 2010, in which the factor separation method has been applied in order to isolate the contributions from aerosol-radiation (AR), aerosol-cloud (AC), and their synergistic effects. The overall ACR effects were to reduce the average cloud liquid water path by 25 g·m−2 (ca. 40% of the baseline) and to increase the downward shortwave radiation by 8 W·m−2 (ca. 3% of the baseline). The spatial difference in response to ACR was large, with ca. 50 W·m−2, 1 K, and 100 m increases in downward shortwave radiation, surface temperature, and planetary boundary layer height (PBLH), respectively, while ca. 60 g·m−2 decrease in cloud liquid water path in central Texas. The AC effect dominated for changes in downward shortwave radiation, cloud liquid water path, wind, and temperature, while both AC and AR effects contributed profoundly to PBLH change. As a result, surface ozone and PM2.5 changed with large temporal-spatial variations. More than a 10 ppbv of surface ozone and a 5 μg·m−3 of PM2.5 difference induced by ACR occurred frequently in the eastern U.S.