Background: Conventionally, vancomycin trough levels have been used for therapeutic drug monitoring (TDM). Owing to the increasing evidence of trough levels being poor surrogates of area under the curve (AUC) and the advent of advanced pharmacokinetics software, a paradigm shift has been made toward AUC-guided dosing. This study aims to evaluate the impact of AUC-guided versus trough-guided TDM on vancomycin-associated nephrotoxicity.Methods: A systematic review was conducted using PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Google scholar, and Cochrane library databases; articles published from January 01, 2009, to January 01, 2021, were retrieved and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Studies that evaluated trough-guided or AUC-guided vancomycin TDM and vancomycin-associated nephrotoxicity were included. Randomeffects models were used to compare the differences in nephrotoxicity.Results: Of the 1191 retrieved studies, 57 were included. Most studies included adults and older adults (n = 47, 82.45%). The pooled prevalence of nephrotoxicity was lower in AUC-guided TDM [6.2%; 95% confidence interval (CI): 2.9%-9.5%] than in trough-guided TDM (17.0%; 95% CI: 14.7%-19.2%). Compared with the trough-guided approach, the AUC-guided approach had a lower risk of nephrotoxicity (odds ratio: 0.53; 95% CI: 0.32-0.89). The risk of nephrotoxicity was unaffected by the AUC derivation method. AUC thresholds correlated with nephrotoxicity only within the first 96 hours of therapy. Conclusions:The AUC-guided approach had a lower risk of nephrotoxicity, supporting the updated American Society of Health-System Pharmacists guidelines. Further studies are needed to evaluate the optimal AUC-derivation methods and clinical utility of repeated measurements of the AUC and trough levels of vancomycin.