There has been an increasing interest in evaluating health effects associated with multiple air pollutants. Identifying the critical factors driving the variation of multiple air pollutants and pollution caused the human health risk are still limited. We selected four typical cities as the study object in the Central Plains Urban Agglomeration (CPUA), China and collected the data of air pollutants, meteorological factors and social development factors over the two years. Our results showed that the air pollutants presented remarkable seasonal variations, according to the principal coordinate analysis (PCoA), the air pollution event often occurred in winter in the CPUA, and the air quality health index (AQHI) values were moderate risk for population health particularly in Zhengzhou and Anyang. The results of the correlation analysis and redundancy analysis (RDA) showed that air pollution and associated health risk was driven by human activities, and was influenced by dominant meteorological factors, such as, rainfall, vapor pressure, relative humidity. These indicated that the air pollution in the CPUA should make the pollutant emission plan according to the region and season to improve the air quality and protect the public health.