Transforming growth factor β (TGF-β)/Smad3 plays a vital role in hypertensive cardiac fibrosis. The long non-coding RNA (lncRNA) Erbb4-IR is a novel Smad3-dependent lncRNA that mediates kidney fibrosis. However, the role of Erbb4-IR in hypertensive heart disease remains unexplored and was investigated in the present study by ultrasound-microbubble-mediated silencing of cardiacErbb4-IRin hypertensive mice induced by angiotensin II. We found that chronic angiotensin II infusion induced hypertension and upregulated cardiacErbb4-IR, which was associated with cardiac dysfunction, including a decrease in left ventricle ejection fraction (LVEF) and LV fractional shortening (LVFS) and an increase in LV mass. Knockdown of cardiacErbb4-IRbyErbb4-IRshort hairpin RNA (shRNA) gene transfer effectively improved the angiotensin II-induced deterioration of cardiac function, although blood pressure was not altered. Furthermore, silencing cardiacErbb4-IRalso inhibited angiotensin II-induced progressive cardiac fibrosis, as evidenced by reduced collagen I and III, alpha-smooth muscle actin (α-SMA), and fibronectin accumulation. Mechanistically, improved hypertensive cardiac injury by specifically silencing cardiacErbb4-IRwas associated with increased myocardialSmad7andmiR-29b, revealing thatErbb4-IRmay targetSmad7andmiR-29bto mediate angiotensin II-induced hypertensive cardiac fibrosis. In conclusion,Erbb4-IRis pathogenic in angiotensin II (Ang II)-induced cardiac remodeling, and targetingErbb4-IRmay be a novel therapy for hypertensive cardiovascular diseases.