The karst plateau is dominated by mountainous and hilly landforms, with low mechanization level of cropland, high difficulty of cultivation, and obvious phenomenon of cropland abandonment, which threatens regional food security. This study aims to analyze the spatial-temporal variation and its driving mechanisms of abandoned cropland in the Karst Plateau in Eastern Yunnan, China (KPEYC) between 2001 and 2020. To achieve this goal, 18 key factors from population, economic environment, cropland attributes, and farming conditions are selected. Moreover, correlation analysis, geodetector, and regression analysis methods are applied from three perspectives: temporal change, spatial distribution and spatial-temporal change. The results show that: (i) The cropland abandonment rate (CAR) in the KPEYC shows a fluctuating trend, with an average value of 9.78%, and the spatial distribution shows a pattern of “high in the center and low in the south and north”. (ii) From the perspective of temporal change, gross value of agricultural production, and gross value of industrial production have the largest correlation coefficients with CAR. (iii) The explanatory power of gross tertiary industrial production, gross value of industrial production, followed by soil thickness. (iv) Gross value of agricultural production, and gross tertiary industrial production are the core driving forces for the spatial-temporal change of CAR. The higher the gross value of agricultural production and gross tertiary industrial production, the lower the CAR. elevation, soil thickness, and traffic mileage are the main driving factors for the spatial-temporal change of CAR. The study indicates that economic factors are decisive for cropland abandonment in the KPEYC. Based on the results, this study can provide decision-making support for local prevention and control of cropland abandonment, and the local community needs to promote land transfer and concentration and local urbanization according to local conditions, improve agricultural policies, improve farming conditions, etc. in order to increase farmers’ enthusiasm for production, promote the rational use of cropland, and solidly push forward ecological restoration and management, optimize ecological spatial patterns, manage serious areas of rocky desertification, and appropriately alleviate the contradiction between people and land.