Background The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right‐sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure‐loaded RV. Here we test the hypothesis that microRNA (miR)‐34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia‐inducible factor‐1α‐vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure. Methods and Results Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia‐inducible factor‐1α expression increased (0.12±0.01 versus 0.22±0.03, P =0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P =0.01). miR‐34a expression was most upregulated in fibroblasts (4‐fold), but also in cardiomyocytes and endothelial cells (2‐fold). Overexpression of miR‐34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P <0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia‐inducible factor‐1α, VEGF A, VEGF B, and VEGF receptor 2. miR‐34a was induced by stretch, transforming growth factor‐β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid‐antimiR‐34a improved RV shortening fraction and survival half‐time and restored capillarity and VEGF expression. In children with congenital heart disease–related RVF, RV capillarity was decreased and miR‐34a increased 5‐fold. Conclusions In summary, miR‐34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia‐inducible factor‐1α‐VEGF axis in RV hypertrophy/RVF, raising the potential for anti‐miR‐34a therapeutics in patients with at‐risk RVs.