This study evaluated the renoprotective effect of evolocumab and telmisartan on obesity-induced comorbidities at the kidney level. The present investigation was conducted using fifty-six male C57BL/6J black mice divided into eight groups, with seven mice per group. Firstly, the control mice were fed a basal control diet and administered evolocumab and/or telmisartan. Second, mice were fed a high-fat diet [HFD] [TD.88137] to induce obesity for 15 weeks. Thirdly, mice were treated with evolocumab and/or telmisartan. Blood samples and renal tissues were collected to evaluate renal function markers, thyroid hormones levels, oxidative stress and antioxidant markers, gene expressions, and histopathological examination. The results showed that mice fed HFD revealed an impairment of renal function markers, including elevated serum levels of creatinine, angiotensin II, and renin. Hypothyroidism was observed as a reduction in serum levels of triiodothyronine [T3] and tetraiodothyronine [T4]. High renal oxidative stress was noticed as an elevation of malondialdehyde [MDA] and nitric oxide [NO] with a reduction in renal antioxidant enzymes as a decreased levels of the reduced glutathione [GSH], glutathione transferase activity [GST], and total antioxidant capacity [TAC]. Additionally, up-regulation of the angiotensin II receptor type 1 gene [AT1-R] and nuclear factor kappa B [NF-κB] gene expression. The histopathological examination represents diffuse tubular degeneration and necrosis. While mice treated with a combination of evolocumab and telmisartan improve renal function markers, as reduction in serum levels of creatinine, angiotensin II, and renin. Thyroid hormones, including serum T3 and T4, were elevated. Alleviation of renal oxidative stress levels and improvement of antioxidant enzyme levels, with down-regulation of AT1r and NF-κB expressions. Also improving the renal histological structure of obese mice. Conclusion: Evolocumab combined with telmisertan is an effective treatment of obesity-induced renal injury by managing the adverse effects correlated with obesity pathophysiology.