The atmospheric infrared sounder (AIRS) provides a robust and accurate data source to investigate the variability of mid-tropospheric CO2 globally. In this paper, we use the AIRS CO2 product and other auxiliary data to survey the spatiotemporal distribution characteristics of mid-tropospheric CO2 and the controlling factors using linear regression, empirical orthogonal functions (EOFs), geostatistical analysis, and correlation analysis. The results show that areas with low mid-tropospheric CO2 concentrations (20°S–5°N) (384.2 ppm) are formed as a result of subsidence in the atmosphere, the presence of the Amazon rainforest, and the lack of high CO2 emission areas. The areas with high mid-tropospheric CO2 concentrations (30°N–70°N) (382.1 ppm) are formed due to high CO2 emissions. The global mid-tropospheric CO2 concentrations increased gradually (the annual average rate of increase in CO2 concentration is 2.11 ppm/a), with the highest concentration occurring in spring (384.0 ppm) and the lowest value in winter (382.5 ppm). The amplitude of the seasonal variation retrieved from AIRS (average: 1.38 ppm) is consistent with that of comprehensive observation network for trace gases (CONTRAIL), but smaller than the surface ground stations, which is related to altitude and coverage. These results contribute to a comprehensive understanding of the spatiotemporal distribution of mid-tropospheric CO2 and related mechanisms.