The application of exogenous melatonin (MT) has shown significant potential in enhancing plant resilience to drought conditions. However, its specific impact on maize tissue mechanisms remains insufficiently elucidated. Here, we compared MT-induced differential responses of maize roots and leaves to drought using integrated metabolome, transcriptome, and physiological analyses. The results indicated that MT treatment positively influenced photosynthetic efficiency and root-shoot biomass in maize seedlings. The contents of ascorbic acid, soluble sugar, and soluble protein increased by 13.3%, 18.8% and 37.1% in roots, and by 58.3%, 34.2% and 64.4% in leaves, respectively. Metabolome profiling identified 394 and 295 differential metabolites in roots and leaves, respectively, and MT notably modulated amino acid metabolites under stress conditions. Key amino acids like proline, methionine, serine, and phenylalanine, among others, were identified as critical contributors to processes including stress defense, energy production, and growth regulation, with a higher accumulation observed in roots compared to leaves. KEGG enrichment analysis of RNA-seq disclosed 23 key genes (e.g. AK, GS, PROC, P5CS, PK, NSE, and TK) related to amino acid biosynthetic regulation in these tissues, determining the tissue-specific accumulation of amino acids. Collectively, MT enhances drought resistance of maize roots and leaves by regulating the stress defense system, energy metabolism, and amino acid pathway. Also, we observed some similarities and differences in MT-modulated genes and metabolites between leaves and roots. These findings provide overall understanding of MT-mediated above- and below-ground physiological and molecular responses of maize to drought environments.