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Heart failure (HF) has limited therapeutic options. In this study, we differentiated the pathophysiological underpinnings of the HF subtypes-HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)-and uncovered subtype-specific therapeutic strategies. We investigated the causal roles of the human proteome and transcriptome using Mendelian randomization on more than 420,000 participants from the Million Veteran Program (27,799 HFrEF and 27,579 HFpEF cases). We created therapeutic target profiles covering efficacy, safety, novelty, druggability and mechanism of action. We replicated findings on more than 175,000 participants of diverse ancestries. We identified 70 HFrEF and 10 HFpEF targets, of which 58 were not previously reported; notably, the HFrEF and HFpEF targets are non-overlapping, suggesting the need for subtype-specific therapies. We classified 14 previously unclassified HF loci as HFrEF. We substantiated the role of ubiquitin-proteasome system, small ubiquitin-related modifier pathway, inflammation and mitochondrial metabolism in HFrEF. Among druggable genes, IL6R, ADM and EDNRA emerged as potential HFrEF targets, and LPA emerged as a potential target for both subtypes.