Cissus is the largest genus in Vitaceae and is mainly distributed in the tropics and subtropics. Crassulacean acid metabolism (CAM), a photosynthetic adaptation for the occurrence of succulent leaves or stems, indicates that convergent evolution occurred in response to drought stress during species radiation. Here, we provided the chromosomal level assembly of Cissus rotundifolia (an endemic species in Eastern Africa) and genome-wide comparison with grape to understand genome divergence within an ancient eudicot family. Extensive transcriptome data were produced to illustrate the genetics underpinning C. rotundifolia’s ecological adaption to seasonal aridity. The modern karyotype and smaller genome of C. rotundifolia (n = 12, 350.69 Mb/1C), which lack further whole-genome duplication, were mainly derived from gross chromosomal rearrangement such as fusions and segmental duplications, whilst sculpted by a very recent burst of retrotransposons activity. Bias on local gene amplification contributed to its remarkable functional divergence with grape and the specific proliferated genes associated with abiotic and biotic responses (e.g., HSP-20, NBS-LRR) enabled C. rotundifolia to survive in a hostile environment. Re-organization of existing enzymes of CAM characterized as diurnal expression patterns of relevant genes further confer to its present thriver in dry savannas.