Updated project metadata. Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies, and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.