Drought stress severely restricts sugarcane (Saccharum spp. cultivars) productivity, a globally vital sugar crop, yet the metabolic basis of its drought resistance remains elusive. Here, we integrated transcriptomic and metabolomic profiles of drought-stressed sugarcane to decipher the regulatory mechanisms. Using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS), we identified 157 differentially expressed genes (DEGs) and 18 differentially accumulated metabolites (DAMs) specifically induced under drought stress. These DEGs/DAMs were co-enriched in 2-oxocarboxylic acid metabolism and branched-chain amino acid (valine/leucine/isoleucine) degradation pathways. Through weighted gene co-expression network analysis (WGCNA), we pinpointed three hub metabolites, tryptophan, proline, and 6-methylquinoline (6-MQ), exhibit a significant correlation with DEGs. Functional validation demonstrated that exogenous 6-MQ application significantly enhanced drought tolerance in sugarcane (17.6 % lower mortality) without growth penalty. Our study not only unravels a novel 6-MQ-mediated regulatory module but also provides valuable metabolite resources for improving drought resistance in sugarcane breeding.