<p><strong>Abstract.</strong> Aerosol optical depth (AOD) has become a crucial metric for assessing global climate change. Although global and regional AOD trends have been studied extensively, it remains unclear what factors are driving the inter-decadal variations in regional AOD and how to quantify the relative contribution of each dominant factor. This study used a long-term (1980&#8211;2016) aerosol dataset from the Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2) reanalysis, along with two satellite-based AOD datasets (MODIS/Terra and MISR) from 2001 to 2016, to investigate the long-term trends in global and regional aerosol loading. Statistical models based on emission factors and meteorological parameters were developed to identify the main factors driving the inter-decadal changes of regional AOD and to quantify their contribution. Evaluation of the MERRA-2 AOD with the combined in-situ measurements of AERONET and the China Aerosol Remote Sensing Network indicated significant spatial agreement on the global scale (<i>r</i>&#8201;=&#8201;0.84, RMSE&#8201;=&#8201;0.14, and MAE&#8201;=&#8201;0.07). In general, MERRA-2 was able to quantitatively reproduce the annual and seasonal AOD trends on both regional and global scales, as observed by MODIS/Terra, albeit some differences were found when compared to MISR. Over the 37-year period in this study, significant decreasing trends were observed over Europe and the eastern United States. In contrast, eastern China and South Asia showed AOD increases, but the increasing trend of the former reversed sharply in the most recent decade. The statistical analyses suggested that the meteorological parameters explained a larger proportion of the AOD variability (20.4&#8201;%&#8211;72.8&#8201;%) over almost all regions of interest (ROIs) during 1980&#8211;2014 when compared with emission factors (0&#8201;%&#8211;56&#8201;%). Further analysis also showed that SO<sub>2</sub> was the dominant emission factor, explaining 12.7&#8201;%&#8211;32.6&#8201;% of the variation in AOD over anthropogenic aerosol&#8211;dominant regions, while BC or OC was the leading factor over the biomass burning&#8211;dominant (BBD) regions, contributing 24.0&#8201;%&#8211;27.7&#8201;% of the variation. Additionally, wind speed was found to be the leading meteorological parameter, explaining 11.8&#8201;%&#8211;30.3&#8201;% of the variance over the mineral dust&#8211;dominant regions, while ambient humidity (including soil moisture and relative humidity) was the top meteorological parameter over the BBD regions, accounting for 11.7&#8201;%&#8211;35.5&#8201;% of the variation. The results of this study indicate that the variation in meteorological parameters is a key factor in determining the inter-decadal change in regional AOD.</p>