Southwest China is the largest continuous karst area in the world, which has suffered from serious ecological degradation. Many researchers have discussed the fragility of karst ecosystem and environment (KEE). However, these studies focused mainly on the particular karst geologic setting and short-term (annual) eco-environmental changes. At longer timescales, knowledge of how KEE responds to external disturbances such as climate changes and human activities is very limited. Based on geochemical analysis of lake sediments in the karst region of Southwest China (KRSC), this paper probes into the evolutionary characteristics of KEE at decadal-centurial timescales. Organic C/N ratios, Sr/Rb ratios and pollen assemblage in Baixian Lake indicate that striking ecoenvironmental deterioration occurred as a result of the drought event between 3.6 ka B.P. and 2.2 ka B.P. The regional vegetation degraded with dwindling herbs, increasing ferns and decreasing terrestrial productivity. Furthermore, the karst ecosystem had not restored to the earlier level even after a long time. Once degradation happens, the karst ecosystem would be unlikely to recover in the short term. Poor water-soil conservation capacity and weak drought resistance of karst soil should be the inherent mechanism of the fragility of terrestrial KEE. Hongfeng Lake has suffered from rapid eutrophication in the last three decades. Reservoirs respond more sensitively to agricultural N and P addition because of abundant dissolved inorganic carbon (DIC) supply from the carbonate catchment in karst region than in non-karst region. A positive feedback loop may develop among elevated primary productivity, higher deposition fluxes of organic matter, anoxia in hypolimnion and enhanced internal P release in aquatic ecosystem. This positive feedback, together with the DIC fertilization effect and sensitivity to agricultural N and P addition, may explain the fragility of aquatic KEE. This paper for the first time presents a long-term evidence for the fragility of both terrestrial and aquatic ecosystem in the KRSC, and provides new insights into the sensitivity and resilience of KEE to climate change and agricultural activities, highlighting the extreme importance of eco-environment protection in karst region.