Background: Drought stress is an adverse factor with deleterious effects on several facets of rice growth. However, the mechanism underlying drought resistance in rice remains unclear. In order to genetically understand the potential molecular mechanism for drought response in rice, a drought sensitive Chromosome Segment Substitution Line (CSSL) PY6, which was constructed by the introgression of genomic segments of drought sensitive variety LAMBAYEQUE1 into drought-resistance variety PR403 via backcrossing, was used to map the QTL locus dss-1 for its sensitive phenotype, and to reveal the impact of dss-1 on the transcriptional profiling of PY6 via RNA-seq and WGCNA (weighted gene co-expression network analysis) analysis. Results: The genetic linkage analysis showed that dss-1 was located on the short arm of chromosome 1 of rice. In contrast to PR403, the over-accumulation of H 2 O 2 and MDA that might result in drought sensitive phenotype was observed in PY6 under drought stress. In the analysis of RNA-seq data, the identified differentially expressed genes (DEGs) mainly enriched in photosynthesis-related GO terms and exhibited a down-regulation pattern of their expressions in both PY6 and PR403 in response to drought stress, indicating that the photosynthesis was greatly inhibited in rice. Further WGCNA analysis constructed a co-expression network with 26 gene modules in which 4 and 3 modules that were highly correlated with H 2 O 2 and MDA, respectively. Likewise, the GO analysis of the differentially expressed hub genes (DEHGs) enriched in H 2 O 2 -correlated modules showed that the photosynthesis related GO terms were consistently over-represented. Furthermore, functional annotation of DEHGs in H 2 O 2 and MDA correlated modules revealed a cross talk between abiotic and biotic stresses. This was reflected by the differential expression alterations of hub genes which were annotated as encoding MYBs, laccases, WRKYs, and PRs family proteins, and ZFP36 were notably observed between PY6 and PR403 in response drought stress. Conclusions: Collectively, we speculated that drought-induced the inhibition of photosynthesis lead to the accumulation of H 2 O 2 and MDA that can trigger the reprogramming the profiling of transcriptome in rice. This included the differential regulation of hub genes that involve in ROS eliminated pathways to prevent the damage of rice plants from oxidative stress.