Background: Drought is an environmental stress that adversely affects maize productivity. However, drought adaption strategies of different maize varieties are not fully clear at the transcriptomic level. In the paper, drought-sensitive SD902 and -resistant SD609 varieties were analyzed to explore transcriptional and physiological alterations to drought stress. Results: The higher SOD, CAT, GSH enzymatic antioxidants, stomatal conductance, transpiration, net photosynthesis rate suggested better performance of SD609 than SD902 variety under drought stress. In transcriptome profiling, a total of 8985 and 7305 difference expression genes (DEGs) were identified in SD902 and SD609 respectively. These genes were overall involved in antioxidation reduce, osmotic adjustment, protein modification (e.g. HSP and chaperone protein), photosynthesis, phytohormone (e.g. ABA, IAA, ethylene), transcription factors (TFs) (e.g. ERF, WRKY, NAC and bZIP) and MAPK (MAPK1/8, MKK4/9 and MKKK17) cascade. Among them, the upregulated genes significantly correlated with stress adjustment, HSPs and chaperone functions might better reduce drought-induced damage in both SD902 and especially SD609. The higher genes expression of IAA, ethylene and electron transfer in SD609 may be closely related to drought-tolerant performance than SD902 plants. Moreover, the misregulation of TFs, MAPK and ABA signaling would appear vital to explain the various sensitivity to drought in both varieties. Conclusion: The more drought-tolerant SD609 presented a beneficial and significantly higher genes expression of stress protection, IAA transduction, photosynthesis compared with drought-sensitive SD902 variety. Our findings provide vital insights into the molecular signatures underpinning drought resistance in maize.