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Background Hypertension is a major modifiable cause of heart failure (HF), yet the metabolic mechanisms linking chronic blood pressure (BP) elevation to cardiac remodeling remain unclear. This study integrated plasma and urinary metabolomics with Mendelian randomization (MR) to identify metabolic mediators and characterize mechanical–metabolic coupling in hypertension-driven HF.Methods Two-step MR and colocalization analyses assessed the effects of systolic (SBP), diastolic (DBP), and pulse pressure (PP) on 1,192 plasma and 1,072 urinary metabolites and their downstream impact on 82 cardiac magnetic resonance (CMR) traits and HF subtypes. The colocolization of HF-related metabolites and HF outcomes was performed. Mediation MR quantified the proportion of BP–HF effects transmitted via specific metabolites, and tier-based prioritization identified high-confidence mediators with therapeutic potential.Results Genetically predicted higher SBP, DBP, and PP were causally associated with increased HF risk independent of major risk factors. Hypertension induced broad metabolic reprogramming across plasma and urine, revealing both shared and compartment-specific metabolites. Distinct protective and detrimental metabolites were identified for all-HF, HFrEF, and HFpEF and validated by stringent MR analyses. Several metabolites correlated with CMR-derived structural remodeling. Mediation MR showed urinary cysteine s-sulfate mediated 8.5% of the DBP–HF effect, while urinary 2-hydroxybutyrate/2-hydroxyisobutyrate mediated 21.6% and 19.3% of the SBP–HF effects for ni-HF and HFrEF, respectively. Druggability screening highlighted metabolite-associated pathways with translational relevance.Conclusions This mediation MR study identifies specific plasma and urinary metabolites as mechanistic mediators of hypertension-driven HF.