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Built-up land sprawl is the most intuitive manifestation and main cause of cultivated land pattern change. Understanding spatiotemporal change and its driving factors in the impact of built-up land sprawl on cultivated landscape eco-security under the urbanization gradient can reveal the nature of cultivated landscape ecological risk caused by urban sprawl and promote the scientific implementation of urban planning and cultivated land protection policies. Taking Yangzhou, a medium-sized city with rapid urbanization, as an example, we used multi-sources data (30 m resolution Landsat images in 1998, 2008, and 2018) to analyze the sprawl intensity and direction of built-up land and cultivated landscape ecological risk areas under the urbanization gradient and the spatiotemporal characteristics of the relationship between them. Further, we employed the boosted regression tree (BRT) model to quantify the effects of geographic, social, and economic factors on the impact of built-up land sprawl on cultivated landscape eco-security under different urbanization gradients. Results showed that built-up land sprawl rate increased first and then decreased from 1998 to 2018, forming the sprawl gradients of no. 1–8, no. 8–16, and no. 16–30 urban circle. Its sprawl direction is mainly 20°–90°, 190°–240°, and 305°–355°, whereas cultivated landscape ecological risk area is a continuous sprawl, and the sprawl gradient and direction of the main risk area are consistent with the built-up land. In 1998–2008, the main areas where built-up land sprawl affects cultivated landscape eco-security are located in no. 1–16 urban circle, 20°–55°. From 2008 to 2018, it was located in no. 16–26 urban circle, 305°–355°. In this process, the influence of geospatial factors decreases gradually over time but increases outwardly with the urbanization gradient. The influence of social factors decreases first with time and then increases with the urbanization gradient outward in space. Economic factors increase with time but decrease with the urbanization gradient. The influence of each factor varies greatly over time and with the urbanization gradient.