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Melatonin exerts pleiotropic physiological functions and diverse disease associations, but its genetic architecture remains largely uncharacterized. Using low-coverage whole-genome sequencing (lcWGS) in 3,605 Han Chinese adults, we identified four independent loci (P < 1 × 10⁻⁷) associated with circulating melatonin (pg/mL)-located within or near LINC01807, PTPRD, EDIL3/NBPF22P, and LMO1/STK33. Conditional analyses indicated that the STAARpipeline single-variant and sliding-window signals were largely driven by these genome-wide association study (GWAS) lead variants, whereas a gene-centric noncoding aggregation signal in the ZSWIM9 promoter region remained independent. These genes showed tissue-specific expression in neural, vascular, and adrenal tissues (GTEx ). The heritability of serum melatonin was estimated at 21.72% (SE = 11.2%, P = 0.029) using GCTA-GREML, with the four independent significant loci collectively explaining 3.40%. Genetic risk score and one-sample Mendelian randomization analyses suggested a protective effect of higher serum melatonin levels on hypertension risk (OR = 0.45, P = 0.015), as well as on systolic (β = - 4.14, P = 0.014) and diastolic blood pressure (β = - 3.10, P = 0.007). Summary-data-based Mendelian Randomization and colocalization analyses suggested that LMO1 and PTPRD may influence hypertension through tissue-specific expression and DNA methylation. These findings reveal novel genetic contributors to melatonin regulation and establish their putative causal relationship with hypertension.