The impacts of climate change have severely affected geosphere, biosphere and cryosphere ecosystems in the Hindu Kush Himalayan (HKH) region. The impact has been accelerating further during the last few decades due to rapid increase in anthropogenic activities such as modernization, industrialization and urbanization, along with energy demands. In view of this, the present work attempts to examine aerosol optical depth (AOD) over the HKH region using the long-term homogeneous MERRA-2 reanalysis data from January, 1980 to December, 2020. The AOD trends are examined statistically with student’s t-test (t). Due to a vast landmass, fragile topography and harsh climatic conditions, we categorized the HKH region into three sub-regions, namely, the northwestern and Karakoram (HKH1), the Central (HKH2) and the southeastern Himalaya and Tibetan Plateau (HKH3). Among the sub-regions, the significant enhancement of AOD is observed at several potential sites in the HKH2 region, namely, Pokhara, Nainital, Shimla and Dehradun by 55.75 × 10−4 ± 3.76 × 10−4, 53.15 × 10−4 ± 3.94 × 10−4, 51.53 × 10−4 ± 4.99 × 10−4 and 39.16 × 10−4 ± 4.08 × 10−4 AOD year−1 (550 nm), respectively, with correlation coefficients (Rs) of 0.86 to 0.93. However, at a sub-regional scale, HKH1, HKH2 and HKH3 exhibit 23.33 × 10−4 ± 2.28 × 10−4, 32.20 × 10−4 ± 2.58 × 10−4 and 9.48 × 10−4 ± 1.21 × 10−4 AOD year−1, respectively. The estimated trends are statistically significant (t > 7.0) with R from 0.81 to 0.91. Seasonally, the present study also shows strong positive AOD trends at several potential sites located in the HKH2 region, such as Pokhara, Nainital, Shimla and Dehradun, with minimum 19.81 × 10−4 ± 3.38 × 10−4 to maximum 72.95 × 10−4 ± 4.89 × 10−4 AOD year−1 with statistical significance. In addition, there are also increasing AOD trends at all the high-altitude background sites in all seasons.