The Great Lakes Depression region basin is among the most sensitive regions to vegetation change due to climate change. This study estimated spatial-temporal changes and relationships in hydro-climate and vegetation dynamics in the basin. Studying the spatial-temporal variation between vegetation dynamics and hydro-climate in this basin is essential for assessing climate change and sustainability. This research involved an examination of the mean yearly air temperature, overall annual rainfall, fluctuations in river discharge, vegetation cover, and alterations in vegetation types within the selected basin stations. This was accomplished through the utilization of hydro-meteorological analysis, satellite assessment, land cover determination, and statistical analysis. Over the course of the study, it was observed that the average annual air temperature increased at all stations (with a positive change of Z = +1.16). The amount of precipitation decreased (Z = −0.79), especially from 2000 to 2014, and its statistical significance decreased. During the study period, average river discharge significantly decreased (Z = −3.51). Due to these combined factors, the lake’s water level also decreased (Z = −2.03). Vegetation cover change varied in high mountains, near river and lake water surfaces, and in arid regions. Changes in air temperature and precipitation in the current year determine vegetation cover. Because of the large amount of precipitation in the summer months from 2000 to 2010 and 2020, the growth of vegetation cover during that period was relatively good. This study was conducted in arid and semi-arid regions of Central Asia and demonstrates the impact of climate change on changes in vegetation cover.