Insulin resistance (IR) seemingly plays a role in chronic kidney disease (CKD). The present study has elucidated the crucial interplay of oxidative stress, inflammatory, apoptotic and profibrotic signaling pathways, linking IR to CKD. The study aimed at investigating the pleiotropic nephroprotective effects of either vildagliptin or vitamin D3 in a fructose/salt-induced IR rat model, highlighting the potential molecular mechanisms underlying their action. Another interesting target was to evaluate the potential capacity of vitamin D3 to potentiate the nephroprotective effects of vildagliptin. Indeed, a state of impaired fasting glucose, IR and compensatory hyperinsulinemia, constellating with significant weight gain, atherogenic dyslipidemia and hyperuricemia was established 6 weeks after fructose/salt consumption. IR rats were then treated orally with vildagliptin (10 mg/kg/day), vitamin D3 (10 µg/kg/day) or their combination for a further 6 weeks. By the end of the 12th week, untreated IR rats displayed significantly declined renal function with parallel interwined renal oxidative stress, inflammatory, apoptotic and profibrotic changes, renal histopathological damages and markedly enhanced collagen fiber deposition. Vildagliptin and vitamin D3 reversed hyperuricemia and exerted a plethora of renal anti-oxidant, anti-inflammatory, anti-apoptotic and anti-fibrotic effects. Our study has introduced a new insight into the role of dipeptidyl peptidase-4 inhibition and silent information regulator 1/5′adenosine monophosphate-activated protein kinase activation in the nephroprotective effects of either agent, elucidating their possible crosstalk with renin angiotensin aldosterone system downregulation. Considering the superadditive renoprotective effects evoked by the combination, vitamin D3 is worth being further investigated as an additional therapeutic agent for preventing IR-induced nephropathy.