Rice (Oryza sativa L.) is an important crop cultivated worldwide, and abiotic stresses limit its productivity. Different approaches were carried out to understand the mechanisms of rice defense responses against abiotic stresses, mainly drought. The NADPH-generating enzymes engaged in response to dehydration and salt stresses during the seedling stage of Nipponbare cultivar were analyzed. Enzyme activities of 6-phosphogluconate dehydrogenase (6PGDH), NADP-dependent aldehyde dehydrogenase, NADP-malic enzyme (NADP-ME) in leaves, and 6PGDH in roots were significantly increased in response to dehydration stress. NADP-ME and NADP-glutamate dehydrogenase activities in roots increased significantly in response to salt stress. These results suggest the involvement of NADPH-generating enzymes in plant responses to dehydration and salinity stresses, and the increased demands of NADPH in plants under abiotic stress can be furnished by enhanced activities of NADPH-producing enzymes. Also, a dehydration-induced protein was detected and identified as serine-hydroxymethyltransferase. This result indicates that serine-hydroxymethyltransferase can play a key role in regulating dehydration response in rice. Moreover, comparative proteomic analyses of CL163 (drought-tolerant), Cheniere (drought-sensitive), and Rex (moderately-drought-sensitive) rice varieties were performed. Drought-responsive proteome changes were profiled in leaves and roots at the seedling stage in response to drought stress imposed by polyethylene glycol (PEG-6000). Eighteen significantly differentially expressed proteins were identified by mass spectrometry. Elongate factor1 alpha and 17.9-kDa classI heat shock protein appear to have different expression patterns between CL163 and Cheniere, which may be attributable to the difference in drought response of the two rice varieties. Furthermore, a compendium of 103 drought resistance genes in rice was compiled to construct and analyze networks formed by associations between genes/proteins and to identify the most significant genes, biological processes/pathways. Genes were classified based on gene ontology and protein class into 26 groups. Forty-two genes were classified as transcription factors. Proteins encoded by the genes were localized in 8 subcellular locations and classified into three classes. Two pathways from KEGG whose genes were overrepresented in the compendium were identified. Gene expression, network presenting pairwise interactions between genes/proteins, and co-expression network were constructed. This study provides a systematic view of the crucial genes that can be contributing collectively to drought tolerance.