Drought stress is the primary environmental factor that negatively influences plant growth and yield in cereal grain crops such as maize (Zea mays L.). Crop breeding efforts for enhanced drought resistance require improved knowledge of plant drought stress responses. In this study, we applied a 12-day water-deficit stress treatment to maize plants of two contrasting (drought tolerant ND476 and drought sensitive ZX978) hybrid cultivars at four (V12, VT, R1, and R4) crop growth stages and we report key cultivar-specific and growth-stage-specific molecular mechanisms regulating drought stress responses in maize. Based on the transcriptome analysis, a total of 3451 and 4088 differentially expressed genes (DEGs) were identified in ND476 and ZX978 from the four experimental comparisons, respectively. These gene expression changes effected corresponding metabolic pathway responses related to drought tolerance in maize. In ND476, the DEGs associated with the ribosome, starch and sucrose metabolism, phenylpropanoid biosynthesis and phenylpropanoid metabolism pathways were predominant at the V12, VT, R2, and R4 stages, respectively, whereas those in ZX978 were related to ribosome, pentose and glucuronate interconversions (PGI), MAPK signaling and sulfur metabolism pathways, respectively. MapMan analysis revealed that DEGs related to secondary metabolism, lipid metabolism, and amino acid metabolism were universal across the four growth stages in ND476. Meanwhile, the DEGs involved in cell wall, photosynthesis and amino acid metabolism were universal across the four growth stages in ZX978. However, K-means analysis clustered those DEGs into clear and distinct expression profiles in ND476 and ZX978 at each stage. Several functional and regulatory genes were identified in the special clusters related to drought defense response. Our results affirmed that maize drought stress adaptation is a cultivar-specific response as well as a stage-specific response process. Additionally, our findings enrich the maize genetic resources and enhance our further understanding of the molecular mechanisms regulating drought stress tolerance in maize. Further, the DEGs screened in this study may provide a foundational basis for our future targeted cloning studies.