Drought stress severely constrains the growth, development, and yield formation of maize (Zea mays L.). As the primary organ for sensing soil water deficit, the root system plays a central role in plant drought adaptation, yet its molecular regulatory mechanisms remain incompletely understood. Here, we performed an integrated transcriptomic and proteomic analysis of roots from the drought-tolerant inbred line PH6WC and the drought-sensitive inbred line KF at both the pre-flowering and mid-flowering stages. Drought stress induced thousands of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in both genotypes, which were predominantly enriched in plant hormone signal transduction, carbon metabolism, cell wall remodeling, reactive oxygen species (ROS) scavenging, and osmotic regulation. Weighted gene co-expression network analysis (WGCNA) identified 13 co-expression modules significantly associated with root traits, physiological indices, and yield-related traits. Core modules were enriched in antioxidative metabolism and hormone responses, carbon metabolism and biosynthesis, root development, and signal transduction and vesicle transport, revealing key regulatory networks underlying maize root responses to drought.