Based on the Sustainable Development Goals (SDGs), this paper proposed a sustainability assessment method, taking Guizhou as an example, to analyze the change characteristics and driving factors of land and water resources sustainability. The findings are as follows. 1) From 2005 to 2020, the sustainability index of land and water resources continued to rise, showing a pattern of “high in the east and low in the west” at the county scale. 2) The change process of the sustainability index of the four sub-targets was different, and the coordination degree presented four changing trends: continuous decline, first decline and then rise, first rise and then fall, and continuous rise. 3) The potential index of water resources and ecological land showed a pattern of “high in the east and low in the west”. The potential index of agricultural land continued to decline, and the potential index of construction land continued to rise. 4) The driving effect of the factors “area under the control of rocky desertification” and “proportion of output value of the tertiary industry” was the strongest. The closer the attributes of the driving factors were, the more obvious the synergistic driving effect was enhanced. Therefore, in karst areas, it is of great significance to carry out control of rocky desertification and improve industrial development level to promote regional sustainable development.