<p>Clinical trials have demonstrated Sodium-glucose cotransporter 2 inhibitors (SGLT2i) antihypertensive effects, yet their underlying mechanisms remain to be fully elucidated. Fibroblast growth factor 21 (FGF21) circulating levels are associated with hypertension in humans. This study aims to investigate the roles of SGLT2i and FGF21 in improving hypertension and their potential mechanisms. A mouse model of Ang II-induced hypertension was established. Wild-type (WT) C57BL/6 mice and FGF21 knockout (FGF21^−/−) mice were sequentially treated with Angiotensin II (Ang II) and dapagliflozin. Blood pressure was monitored. Cardiac structure was assessed using echocardiography. Serum FGF21 levels were measured, and the expression of fibroblast growth factor receptor 1 (FGFR1) in the thoracic aorta was quantified. Vascular pathology and oxidative stress responses were evaluated. Human aortic smooth muscle cells (HASMCs) were treated with Ang II or SGLT2i, and FGF21 was knocked down in HASMCs to explore its mechanism of action. SGLT2i increased the expression of FGF21 and FGFR. SGLT2i improved Ang II-induced systolic blood pressure elevation, myocardial hypertrophy, vascular wall thickening, fibrosis, and oxidative stress in WT mice. These protective effects were reduced in FGF21^−/− mice. Knockdown of FGF21 in HASMCs abolished the SGLT2i-induced upregulation of antioxidant markers and the downregulation of TGF-β and fibrosis-related proteins. SGLT2i-mediated blood pressure-lowering and vascular protective effects are primarily achieved through the activation of the FGF21/FGFR1.</p> Graphical Abstract <p></p>