Background and Purpose: Hypertensive vascular remodeling (VR) is responsible for end-organ damage and is the result of increased extracellular matrix accumulation and excessive vascular smooth muscle cell (VSMC) proliferation. MicroRNA-26a (miR-26a), a non-coding small RNA, is involved in multiple cardiovascular diseases. We aimed to validate the effect and mechanisms of miR-26a in hypertensive VR. Experimental Approach: Spontaneously hypertensive rats (SHRs) were injected intravenously with recombinant adeno-associated virus-miR-26a. In vitro experiments, angiotensin II (AngII)-induced VSMCs were transfected with miR-26a mimic or inhibitor. Key Results: We found miR-26a downregulated in the thoracic aorta and plasma of SHRs. Overexpression of miR-26a inhibited extracellular matrix deposition by targeting connective tissue growth factor (CTGF) and mitigated VSMC proliferation by regulating the enhancer of zeste homolog 2 (EZH2)/p21 pathway both in vitro and in vivo. AngII-mediated Smad3 activation suppressed miR-26a expression, which in turn promoted Smad3 activation via targeted regulation of Smad4, leading to further downregulation of miR-26a. Conclusion and Implications: Our study reveals that AngII stimulates a Smads/miR-26a positive feedback loop, which further reduces miR-26a expression, leading to collagen production and VSMC proliferation and consequently, VR. MiR-26a has an antagonistic effect on hypertensive VR and can be a strategy for treating hypertensive VR.