Glacier mass balance is one of the most direct indicators reflecting corresponding climate change. In the context of global warming, most glaciers are melting and receding, which can have significant impacts on ecology, climate, and water resources. Thus, it is important to study glacier mass change, in order to assess and project its variations from past to future. Here, the Karakoram, one of the most concentrated glacierized areas in High-Mountain Asia (HMA), was selected as the study area. This study utilized SRTM-C DEM and ICESat-2 to investigate glacier mass change in the Karakoram, and its response to climatic and topographical factors during 2000–2021. The results of the data investigation showed that, overall, the “Karakoram Anomaly” still exists, with an annual averaged mass change rate of 0.02 ± 0.09 m w.e.yr−1. In different sub-regions, it was found that the western and central Karakoram glaciers gained ice mass, while the eastern Karakoram glaciers lost ice mass in the past two decades. In addition, it was discovered that the increasing precipitation trend is leading to mass gains in the western and central Karakoram glaciers, whereas increasing temperature is causing ice mass loss in the eastern Karakoram glacier. Generally, decreasing net shortwave radiation and increasing cloud cover in the Karakoram restricts ice mass loss, while topographical shading and debris cover also have dominant impacts on glacier mass change.