Purpose <p>Cisplatin-based combination chemotherapy is the mainstay treatment strategy in various forms of carcinomas and sarcomas. However, its dosage and therapeutic efficacy are significantly limited by its&#xa0;nephrotoxicity. Based on metformin renal benefits in different studies, the study aims to determine safety and the potential nephroprotective effect of metformin when used with cisplatin in patients with bladder cancer.</p> Methods <p>This was a prospective, randomized, parallel, controlled, open-label study in which 78 chemotherapy naïve bladder cancer patients aged 18–65&#xa0;years and would receive gemcitabine/cisplatin regimen were selected and randomly assigned to treatment or control group in 1:1 allocation. Both groups were receiving cisplatin standard-of-care regimen, whereas metformin (500&#xa0;mg, twice daily) was added to the treatment group's regimen only. Patients were prospectively followed up for four cycles of gemcitabine/cisplatin with assessment of renal function tests, serum neutrophil gelatinase-associated lipocalin (NGAL), cystatin-c, and metformin's adverse effects.</p> Results <p>Serum creatinine, serum NGAL, and cystatin-C significantly increased in the control group only (<i>P</i> &lt; 0.001). Estimated glomerular filtration rate (eGFR) significantly declines in the control group only (<i>P</i> &lt; 0.001). On the contrary, serum NGAL significantly improved in the treatment group (<i>P</i> = 0.02) with stable and normal mean value of serum creatinine, eGFR, and cystatin-C without a concomitant significant increase in adverse events, such as hypoglycemia, gastrointestinal symptoms, or weight loss compared to the control group.</p> Conclusion <p>Metformin prevented renal damage and deterioration in kidney function in cisplatin-treated patients. Therefore, it is a promising agent in reducing cisplatin-induced nephrotoxicity. The study was registered in ClinicalTrials.gov on <i>December, 16, 2023</i>, Identifier Number NCT06215976.</p>