Melatonin (MT) serves an indispensable function in plant development and their response to abiotic stress. Although numerous drought-tolerance genes have been ascertained in wheat, further investigation into the molecular pathways controlling drought stress tolerance remains necessary. In this investigation, it was observed that MT treatment markedly enhanced drought resistance in wheat by diminishing malondialdehyde (MDA) levels and augmenting the activity of antioxidant enzymes POD, APX, and CAT compared to untreated control plants. Transcriptomic analysis disclosed that melatonin treatment activated the tryptophan metabolism and flavonoid biosynthesis pathways. Furthermore, quantitative reverse transcription PCR (qRT-PCR) outcomes validated that the expression trends of these differentially expressed genes aligned with the transcriptomic data. Metabolomic profiling identified alterations in the abundance of several metabolites, including tryptamine, MT, formylanthranilate, 3-hydroxyanthranilate, 6-hydroxymelatonin, naringenin chalcone, astragalin, pinbanksin, and caffeoyl quinic acid. Co-expression analysis suggested that various transcription factors-encompassing AP2/ERF-ERF, WRKY, bZIP, C2H2, bHLH, NAC, and MYB-participated in controlling the differentially expressed genes across multiple pathways. Ultimately, these findings highlight that exogenous MT application bolsters wheat's drought tolerance through the modulation of tryptophan metabolism and flavonoid biosynthesis. These insights provide novel perspectives on the molecular frameworks mediating MT's effect on drought resistance and pinpointing candidate genes for potential genetic enhancement programs in wheat.