Abstract Background: There is limited research on the risk of acute renal failure (ARF) due to Drug-Drug Interaction (DDI) between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and potentially nephrotoxic drugs. This study analyzed the adverse events of ARF due to concomitant use of sodium-glucose cotransporter 2 inhibitors and potentially nephrotoxic drugs based on data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) with the aim of providing a reference for the safe and rational use of such drugs. Methods: Data mining of ARF signals generated by drug combinations was performed using the ratio of reported odds (ROR) method and further validated using additive, multiplicative, and combined risk ratio (PRR) models. A subset of data based on monotherapy cases was also analyzed. Results: A total of 4,417,195 adverse event reports were included in our analysis, and 65,945 ARF events were found to be associated with SGLT2i and potentially nephrotoxic drugs. We observed a significantly higher incidence of ARF with the combination of dapagliflozin and cefazolin [adjusted ROR (95%CI) 59.63 (9.96,356.87)], Additive Model 0.53, Multiplicative Model 8.36, [PRR (Combination Risk Ratio) 8.53]. Additionally, consistent associations were found when analyzing dapagliflozin in combination with apixaban and tacrolimus, engeletin with torasemide, allopurinol, and naproxen, and canagliflozin with vancomycin and furosemide. Conclusion: Our analysis of the FAERS data identified varying degrees of ARF risk associated with coadministration with SGLT2i and potentially nephrotoxic drugs, highlighting the need for vigilance with both drugs in clinical practice.