The Twain-Hu basin (THB), covering the lower plain of Hubei and Hunan provinces in Central China, has experienced severe air pollution in recent years. However, the terrain effects of such sub-basin on air quality over the THB have been incomprehensibly understood. A heavy PM2.5 pollution event occurred over the THB during 4–10 January 2019. By using the observations and WRF-Chem simulations, we investigated the underlying mechanisms of sub-basin effects on the air pollution with several sensitivity experiments. Observationally, air pollution in the western THB urban area with an average PM2.5 concentration of 189.8 μg m−3, which was more serious than the eastern urban area with the average PM2.5 concentration of 106.3 μg m−3, reflecting a different influence of topography on air pollution over the THB. Simulation results revealed that the terrain effect can contribute 12.0% to increasing the PM2.5 concentrations in the western THB, but slightly mitigate the pollution extent in the eastern THB with the contribution of −4.6% to PM2.5 during the heavy pollution episode. In particular, the sub-basin terrain was conducive to the accumulation of PM2.5 by regional transport with the contribution of 39.1 %, and contrarily lowered its local pollution by −57.0% via the enhanced atmospheric boundary layer height and ventilation coefficients. Given a heavy air pollution episode occurring over the THB, such inverse contribution of terrain effects reflected a unique importance of sub-basin topography in regional transport of air pollutants for air pollution in central China.