Rapid urbanization in China has elicited a change in the pattern of settlement landscape, particularly for the plain area with its long history of human settlement. However, relevant research is lacking. By employing the spatial analysis method of GIS and remote sensing image processing technology of ENVI, we analyzed the characteristics of changes of Kaifeng, Shangqiu, and Zhoukou in the Eastern Plain of Henan Province with respect to settlement size and spatial distribution on a meso-scale from 1972 to 2015. The results indicated that, first, the number of settlement patches decreased, whereas their sizes gradually expanded, and the built-up areas of the respective cities expanded noticeably. Furthermore, the village patches surrounding the urban areas experienced a greater expansion than other village patches. Second, the spatial distribution of settlement patches in the study area exhibited a clustered distribution; however, the degree of agglomeration declined in 2015. The kernel density distribution of settlement patches was stable, although multi-core diffusion existed in some regions, and the density distribution was different among cities. Third, the patch shape index (PSI) revealed that the narrow or tortuous patches were spatially scattered, and the shape of settlements was relatively regular in 2015. Finally, as distance from rivers and roads increased, the total size and number of settlement patches decreased; however, the effect of roads on settlement distribution was only detected in certain regions. The settlement patches located within the 6 km buffer zone of the respective central cities were affected by development of the urban areas. The results presented here could assist in the optimal layout of settlement landscape and the intensive development of settlement land-use in the Eastern Plain of Henan Province.