Objective: In diabetes mellitus, the activation of the intrarenal reninangiotensin system (RAS) is implicated in the pathogenesis of diabetic nephropathy (DN) and hypertension. Angiotensin II type 1 receptor (AT1R), a RAS component is downregulated by curcumin (CUR) under pathologic condition. We aimed to investigate the effect of tetrahydrocurcumin (THC), a stronger antioxidant hydrogenated, from CUR on intrarenal RAS expression, kidney injury and systolic blood pressure (SBP) in high-fat diet (HFD)- fed mice. Methods: Eight-week-old C57BL/6J mice were fed with normal diet (ND) or HFD for 12 weeks, and THC (50 or 100 mg/kg/day) was intragastrically administered along with HFD initiation. During experimental period, physiologic and metabolic changes of those mice were monitored. At the end, mice were sacrificed, and sample analyses were conducted. Results: Compared with ND group, HFD-fed mice exhibited hyperglycemia, insulin resistance and hyperlipidemia (p < 0.01). Kidney injury was also found in those mice as the evidence of increasing albumin to creatinine ratio (ACR), glomerular hypertrophy and mesangial expansion, with renal upregulation of angiotensin converting enzyme (ACE), AT1R, NADPH oxidase-4 and renal inflammation markers (ICAM-1 and MCP-1). SBP monitoring during 12 weeks of the experiment revealed that HFD gradually elevated SBP and reached the significant difference compared with ND at 10 weeks (p < 0.05). High SBP was observed accompanied with vascular remodeling including vascular wall thickening and increased vascular cross-sectional area (p < 0.05 vs. ND). THC at 100 mg/kg/day effectively suppressed intrarenal RAS activation, improved insulin sensitivity, and prevented vascular remodeling, thereby attenuating kidney injury. Conclusion: Taken together, our results suggest that supplementation with THC may have beneficial effects for preventing kidney injury and high SBP through the modulation of intrarenal RAS activation in HFD-fed mice.