Cuticular wax and cutin are directly involved in the mechanisms by which plants acclimate to water-limited environments. However, how the two lipid forms balance their contributions to plant drought-tolerance is still not clear. The present study examined the responses of cutin monomers and cuticular waxes to drought stress in two sorghum (Sorghum bicolor (L.) Moench) cultivars, drought-tolerant cv. Kangsi and drought-sensitive cv. Hongyingzi, by combining lipidomic and transcriptomic analysis. Drought increased total cutin contents by 41.3%, the contents of alkanoic acids by 72.6% and 2-hydroxyacids by 117.8% in Kangsi but unchanged those in Hongyingzi. The abundance of cutin monomers were relatively stable for cv Hongyingzi, excepting for a decrease of ω-hydroxyacids from 35.0% to 27.4% in drought-stressed plants. However, for cv Kangsi, the abundance of ω-hydroxyacids decreased from 36.8% to 21.0% and that of alkanoic acids increased from 30.5% to 37.1% in drought-stressed plants. Drought increased total wax coverage in Hongyingzi but reduced it in Kangsi. However, the abundance of aldehydes decreased from 51.2% to 39.3% in drought-stressed cv Kangsi, but increased from 25.2% to 36.1% in drought-stressed cv Hongyingzi. A decrease of sterols (by 76%) and an increase of primary alcohol (by 443%) was also observed in drought-stressed cv Hongyingzi. Transcriptome analysis also revealed that many genes implicated by homology in cutin monomer and cuticular wax biosynthesis also differed in their responses to drought stress between the two sorghum cultivars. Therefore, sorghum cultivars differed in their mechanisms in adjusting chemical profiles of both cutin and cuticular wax under water deficit condition.