Purpose The study aimed to investigate the potential nephroprotective efects of vitamin D3 in metabolic syndrome (MetS) and the molecular basis of the underlying mechanisms of its action. Methods MetS was induced in adult male Wistar rat‏s by adding fructose (10%) to every day drinking water and salt (3%) to the diet. Six weeks after fructose/salt consumption, fasting serum lipid profle and uric acid levels were determined, an oral glucose tolerance test (OGTT) was performed and kidney function was checked. MetS rats were then treated orally with vitamin D3 (10 µg/kg/day) for 6 weeks. At the end of the study period (12 weeks), the OGTT test was reperformed, anthropometrical parameters were measured, urine, blood and tissue samples were collected and the animals were euthanised. Results The incidence of MetS was confrmed 6 weeks after fructose/salt consumption, when the rats exhibited signifcant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia and impaired glucose tolerance. After 12 weeks, MetS rats displayed markedly declined renal function alongside with extravagant renal histopathological damages and interstitial fbrosis. Furthermore, signifcantly enhanced renal oxidative stress and infammation were manifested. Vitamin D3 supplementation in MetS rats signifcantly reversed all the above-mentioned deleterious efects. Conclusion The study has indeed provided mounting evidence of the promising therapeutic potential of vitamin D3 against development and progression of MetS-induced nephropathy. A new insight has been introduced into the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5′adenosine monophosphate-activated protein kinase activation in the renoprotective efects of vitamin D3.