Karst peak-cluster depressions are the largest karst landforms in southwest China. Compared with other karst landforms, the hydrothermal resources in peak-cluster depressions are relatively abundant. Due to the heterogeneity of this region, the investment and governance for rocky desertification treatment is extensive, and the treatment and governance technologies are lack of robustness and pertinence. Therefore, it is urgent to develop the natural regionalization for rocky desertification treatment in karst peak cluster depression to enhance the sustainability and pertinence of rocky desertification treatment. In this study, with the combination of the heterogeneity of geological setting, climate, geomorphic and topographic conditions of karst peak-cluster depression, we proposed a method to regionalize peak-cluster depression into different subregions. Firstly, based on the corrected geological map, karst peak-cluster depressions were divided into non-karst area dominated by clastic rocks and karst area dominated by carbonate rocks. Then, according to the characteristics of heterogeneous climate conditions, the karst area was divided into the atypical peak-cluster depression area of southeastern Yunnan and southwestern Guangxi in southwest monsoon and typical peak-cluster depression area in East Asia monsoon. Furthermore, the typical peak-cluster depression areas of East Asia monsoon were further divided into four subregions, including the shallow dish-shaped awl-peak depression subregion in southwestern Guizhou plateau, funnel-shape awl-peak depression areas in southern Guizhou and Northern Guangxi, funnel-shaped awl-tower depression subregion in central Guangxi and the southern giant slope areas, and shallow dish-shaped awl and tower peak depression subregion in southern Guangxi hills in accordance with the geomorphological location and topographic features. The regionalization results showed that the natural geographical characteristics of each subregion were apparently distinct. The landforms in non-karst area dominated by clastic rocks have gentle slope and thick soil, where population pressure is relatively relaxed. The atypical peak-cluster depression area of southeastern Yunnan and southwestern Guangxi in Southwest monsoon is dominated by normal mountains because of the significantly impacts of southwest monsoon climate. The severe and extremely severe rocky desertification are serious in the funnel-shaped awl and tower depression subregion in central Guangxi and the southern giant slope areas, while the rocky desertification in this subregion reduced more faster and the treatment efficiency are the most significant. The contradiction between human and land is the most acute in the shallow dish-shaped awl-peak depression areas in southwestern Guizhou plateau, and the problem of rocky desertification in this area is also serious. The proportion of rocky desertification treatment is relatively low and karst landscape resources are rich in the funnel-shaped awl-peak depression subregion in southern Guizhou, northern Guangxi and the northern giant slope areas. The hydrothermal resources are the most abundant and the relationship between human and land is relatively relaxed in the shallow dish-shaped awl and tower peak depression subregion in southern Guangxi hills. The natural regionalization for rocky desertification treatment clarifies the homogeneity and heterogeneity of natural and socio-economic conditions in different karst peak-cluster depression subregions, which will enhance the regional pertinence and sustainability of rocky desertification treatment.