Background: Nephrotoxicity remains a significant concern in the management of critically ill patients receiving antibiotic therapy. The combination of Vancomycin and Piperacillin-Tazobactam (VPT) is frequently employed to combat multidrug-resistant infections. However, emerging evidence suggests a potential increase in the risk of acute kidney injury (AKI) associated with this combination. This study aims to systematically review and analyze the nephrotoxic risk of the VPT combination in comparison to Vancomycin with Cefepime (VC) combination therapy. Methodology: We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed in databases including PubMed and Google Scholar for studies published until 2024. Studies that reported AKI incidence in patients treated with VPT, or VC were included. The data were analyzed using random-effects models to estimate pooled incidence rates of AKI. Subgroup analyses were performed based on patient demographics and baseline renal function. Results: A total of six studies involving 23 794 patients were included in the analysis. The pooled incidence of AKI in the VPT group was found to be 29.9% (95% CI: 25.3%-38.4%), significantly higher than that of the VC (22.7%) (P < .05). A comparative analysis demonstrated a significantly higher risk of AKI in patients on VPT compared to VC (1.503; 95% CI: 1.221-1.849 P < .001). Conclusion: The findings of this study underscore a significant increase in the risk of AKI associated with the Vancomycin and Piperacillin-Tazobactam combination in critically ill patients. Clinicians should exercise caution when prescribing this combination, particularly for patients with pre-existing renal dysfunction.