Accurate and reliable land cover information is vital for ecosystem management and regional sustainable development, especially for ecologically vulnerable areas. The South China Karst, one of the largest and most concentrated karst distribution areas globally, has been undergoing large-scale afforestation projects to combat accelerating land degradation since the turn of the new millennium. Here, we assess five recent and widely used global land cover datasets (i.e., CCI-LC, MCD12Q1, GlobeLand30, GlobCover, and CGLS-LC) for their comparative performances in land dynamics monitoring in the South China Karst during 2000–2020 based on the reference China Land Use/Cover Database. The assessment proceeded from three aspects: areal comparison, spatial agreement, and accuracy metrics. Moreover, divergent responses of overall accuracy with regard to varying terrain and geomorphic conditions have also been quantified. The results reveal that obvious discrepancies exist amongst land cover maps in both area and spatial patterns. The spatial agreement remains low in the Yunnan–Guizhou Plateau and heterogeneous mountainous karst areas. Furthermore, the overall accuracy of the five datasets ranges from 40.3% to 52.0%. The CGLS-LC dataset, with the highest accuracy, is the most accurate dataset for mountainous southern China, followed by GlobeLand30 (51.4%), CCI-LC (50.0%), MCD12Q1 (41.4%), and GlobCover (40.3%). Despite the low overall accuracy, MCD12Q1 has the best accuracy in areas with an elevation above 1200 m or a slope greater than 25°. With regard to geomorphic types, accuracy in non-karst areas is evidently higher than in karst areas. Additionally, dataset accuracy declines significantly (p < 0.05) with an increase in landscape heterogeneity in the region. These findings provide useful guidelines for future land cover mapping and dataset fusion.