The adaptation to aerobic environments enables upland rice to produce a sustainable grain yield under suboptimal conditions. In order to understand the molecular mechanisms involved in providing the adaptation of upland rice to aerobic environments, we previously developed introgression lines (ILs) with the irrigated rice variety Minghui63 (MH63) as the recipient parent and the upland rice variety Luyin46 (LY46) as the donor parent for subsequent identification of the relevant genes. In this study, IL-U135 was analyzed in detail because of its adaptation to aerobic conditions. Transcriptome profiling revealed 20 and 8 differentially expressed genes (DEGs) between IL-U135 and MH63 under anaerobic and aerobic conditions, respectively. In contrast, 306 and 188 DEGs were identified between LY46 and MH63 under anaerobic and aerobic conditions, respectively. Gene ontology (GO) analysis indicated that the adaptation of upland rice to aerobic environments is intimately associated with CLV3/ESR-related (CLE) signal transduction pathways, CLAVATA1 kinase activity, and salicylic acid related metabolism biosynthetic pathways. The IL-U135, LY46 and MH63 genomes were resequenced to map the genes responsible for adaptations to aerobic conditions. One the basis of an integrated analysis of the transcriptomic and genomic profiles, we propose that genes encoding an NBS-LRR protein (LOC_Os11g10570) and an ATP-binding protein (LOC_Os11g31480) may contribute to the adaptation of upland rice to aerobic environments. Our results may provide new insights into the molecular mechanism underlying the adaptation of rice to aerobic conditions.