<p>Cropland expansion has profound importance in maintaining food and grain security. It is also one of the most active transformations to alter the characteristics of earth’s surface. The increasing frequency of cropland expansion from occurring is anticipated owing to the enforcement of cropland protection policies worldwide. Understanding the spatial patterns, trajectories, and driving factors can significantly promote the perfection of cropland protection policies. Thus, choosing the three urban agglomerations in the Yangtze River Economic Belt as a case, this study explored the cropland expansion trajectories and further investigated their spatial heterogeneity in 2000–2020 through the combination of the spatial autocorrelation analysis and landscape expansion index. Then, the driving factors of cropland expansion trajectories and the interaction effects of driving factors were identified by the factor and interaction detector modules in the geographical detector model. Results demonstrated the following: (1) three urban agglomerations expressed a considerable amount of cropland expansion, and the expansion trajectories can be identified as the following three categories: outlying, infilling, and edge-expansion trajectories; (2) spatial heterogeneity exists in the spatial patterns of different cropland expansion trajectories, and the infilling and edge-expansion trajectories display noticeable spatial cluster patterns; (3) the cropland expansion trajectories are affected by socioeconomic and environmental factors; nonetheless, except for the infilling trajectory, the <i>q</i>-value is relatively small; (4) the interaction effects of driving factors include nonlinear and bilinear enhancements, and nonlinear enhancement has the dominant position. These findings can help the government and decision-makers improve the existing cropland protection policies by considering the cropland expansion trajectory and exploiting the synergistic role of multiple factors.</p>