The aim of this study is to investigate the impact of 6-gingerol (6-G) on oxidative stress in high-fat high-fructose (HFHF) diet-induced metabolic syndrome (MetS) in rats. Male Sprague-Dawley rats were randomly divided into five groups (n = 5). The control group received a standard diet. The MetS group received the HFHF diet for 16 weeks and, at Week 8, received a single dose of streptozotocin at 22 mg/kg body weight (b.w.). After eight weeks of HFHF diet feeding, the rats were dosed orally with 6-G (50, 100, or 200 mg/kg/day) once daily for another eight weeks. Urine samples were collected for N-acetyl-β-D-glucosaminidase (NAG) and creatinine analysis, whereas kidney tissue was obtained for histological evaluation and quantitative real-time polymerase chain reaction studies for p47phox, p67phox, NOX2, and NOX4. At the end of the study, the urine NAG/creatinine ratio was significantly decreased in the 6-G groups at all three doses. The 6-G treatment at all three doses markedly suppressed messenger RNA expression of p47phox, p67phox, NOX2, and NOX4. This was associated with a substantial decrease in tubulointerstitial inflammatory cells, fibrotic area, and lipid droplets in rats receiving the HFHF diet and 6-G Treatment. 6-G could attenuate MetS-induced kidney injury via anti-oxidant activity, leading to improved kidney damage. © 2025 Endah Wulandari et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).