Geographical environment and climate change are basic factors for spatial fluctuations in the global distribution of air pollutants. Against the background of global climate change, further investigation is needed on how meteorological characteristics and complex geographical environment variations can drive spatial air pollution variations. This study analyzed the response of air pollutant emissions to climate change and the potential effects of air pollutant emissions on human health by integrating the air pollutant emission simulation model (GAINS) with 3 versions and CMIP5. The mechanism by which meteorological characteristics and geographical matrices can drive air pollution based on monitoring data at the site-scale was also examined. We found the total global emission of major air pollutants increased 1.32 times during 1970–2010. Air pollutant emissions will increase 2.89% and 4.11% in China and developed countries when the scenario of only maximum technically feasible reductions is performed (V4a) during 2020–2050. However, it will decrease 19.33% and 6.78% respectively by taking the V5a climate scenario into consideration, and precipitation variation will contribute more to such change, especially in China. Locally, the air circulation mode that is dominated by local geographical matrices and meteorological characteristics jointly affect the dilution and diffusion of air pollutants. Therefore, natural conditions, such as climate changes, meteorological characteristics and topography, play an important role in spatial air pollutant emissions and fluctuations, and must be given more attention in the processes of air pollution control policy making.