The Yunnan-Guizhou Plateau, located in the ecologically fragile Southwest Karst region, faces urgent ecological and environmental challenges. Its unique topography and landforms have contributed to severe soil erosion, resulting in a highly vulnerable ecosystem and exacerbating the issue of rocky desertification. Furthermore, the Yunnan-Guizhou Plateau plays a critical role as a significant ecological barrier in the southwestern part of China, highlighting its pivotal contribution to the nationwide endeavor to establish a resilient national ecological civilization. It is important to understand the status of ecological environment and ecological restoration benefits in the Yunnan-Guizhou Plateau in the past 20 years. Comprehensively evaluating the ecological restoration benefits and clarifying the natural-socioeconomic driving mechanisms is of great significance in maintaining regional ecological security and achieving sustainable development goals. Nevertheless, there are few case studies on the quantitative analysis of the restoration degree and its influencing factors over a time series at the regional scale. Thus, this study aims to evaluate the ecological restoration benefits of the Yunnan-Guizhou Plateau region from 2000 to 2019 based on multi-source remote sensing data and methods including model simulation and time-series trend analysis. We assessed the ecological restoration benefits on three levels, which are ecosystem macrostructure, ecosystem quality, and ecosystem services. The random forest method was used to explore the natural-socioeconomic influencing factors of ecological restoration. The results showed that: (1) The ecosystems macrostructure changed significantly, as manifested in the increase of forest, grassland and settlement area, as well as in the decrease of farmland area. (2) The restoration tendencies of ecosystem quality and ecosystem services were overall stable and improving, except for some areas that were getting worse. (3) Overall, ecosystem restoration degrees were high. Areas with moderate and above recovery levels accounted for 35.84% of the total area, while areas with worsening and below recovery levels were the least, accounting for 7.54% of the total area. (4) Ecological background characteristics such as topography, climate, and soil properties were the most important factors for ecological restoration. Meanwhile, at the local level, human activities such as afforestation area and population density change rate played a crucial role in ecological restoration. Therefore, regional ecological background and scale effects should be comprehensively considered in ecosystem management and ecological restoration projects. Adopting targeted restoration measures is crucial to achieve win-win situations for ecological and socio-economic development. The research findings can serve as a valuable scientific foundation for the preservation and management of the ecosystem in the Yunnan-Guizhou Plateau.