Objective <p>N-acetylcysteine (NAC) has antioxidant effects in reducing acute kidney injury. This study systematically reviewed and assessed the efficacy of NAC in preventing antimicrobials induced nephrotoxicity.</p> Methods <p>Pubmed, Embase, Web of Science, and the Cochrane Library were searched extensively for relevant studies that evaluating NAC on antimicrobials induced nephrotoxicity until June 1, 2024. Eligible records were screened according to the inclusion and exclusion criteria. The odds ratio (OR) was selected to evaluate the effect of NAC on nephrotoxicity. We pooled the extracted data using a random effects model.</p> Results <p>Three randomized controlled trials were included in the analysis. The pooled results showed that NAC could reduce the incidence of antimicrobials induced nephrotoxicity (OR = 0.487, 95% CI = 0.258, 0.918, <i>P</i> = 0.03, <i>I</i>² = 0%). Serum creatine (Scr) on Day 2 was significantly decreased in the NAC group compared to the placebo group (SMD, − 0.298; 95%CI, − 0.585 to − 0.010; <i>I</i>² = 23%; <i>P</i> = 0.04). No difference was observed in blood urea nitrogen (BUN), and creatinine clearance (CrCl).</p> Conclusion <p>In this meta-analysis, NAC was associated with a benefit in the prevention of antimicrobials induced nephrotoxicity. However, large-scaled and well-designed RCTs are required in the future.</p>