Genome size, the total amount of DNA content in the cell nucleus, varies greatly among flowering plants. One factor underlying this variation is the environment under which plants evolve. Given this premise, harsh environmental conditions in arid regions may profoundly influence genome evolution. However, the specific impact of aridification on genome size evolution, particularly for African lineages, remains largely unexplored. Here, we investigate linkages between genome size evolution and ecological adaptation using the genus Cyphostemma in the grape family (Vitaceae) as a model. Cyphostemma species exhibit genome size expansion and remarkable morphological traits in arid environments, including succulent stems or leaves and loss of tendrils. Our biogeographic reconstruction, based on substantial taxon sampling (112 of 200 species), reveals that Cyphostemma originated in continental Africa during the late Eocene to Oligocene and has undergone rapid radiation since the middle Miocene, coinciding with intensified aridification and geological activity in eastern Africa. Incorporating extensive data on traits, habitats, genome size, and chromosome numbers, we show that Cyphostemma species with the largest genomes are succulent polyploids restricted to nutrient-rich limestone outcrops. Broad-scale analyses across eudicots further confirm that larger genomes are significantly associated with both succulence and arid habitats. Our findings reveal a strong association between genome size expansion, polyploidy, and adaptive traits, indicating that genome size is a hitherto neglected trait associated with the radiation of succulent plants during the African aridification in the Cenozoic.