Maize (Zea mays) is an important food and forage crop, as well as an industrial raw material, that plays important roles in agriculture and national economies. Drought stress has negative effects on seed germination and seedling growth, and it decreases crop production. In this study, we selected two maize inbred lines with different drought-tolerance levels: drought-tolerant 287M and drought-sensitive 753F. The physiological results showed that drought stress resulted in a large accumulation of reactive oxygen species (ROS) in maize root cells. However, in 287M, the activity levels of the ROS scavenging enzymes superoxide dismutase and ascorbate peroxidase also increased, resulting in a higher ROS scavenging ability than 753F. We used Illumina RNA sequencing to obtain the gene expression profiles of the two maize inbred lines at the seedling stage in response to drought stress. The transcriptome data were analyzed to reveal the mechanisms underlying the drought tolerance of 287M at the gene regulatory level. The differences in drought tolerance between 287M and 753F may be associated with different ROS scavenging capabilities, signal interaction networks, and some transcription factors. Our results will aid in understanding the molecular mechanisms involved in plant responses to drought stress.