Background <p>Nephrotoxicity may increase the risk of neonatal mortality. Early identification of risk factors for nephrotoxicity is essential to improve clinical outcomes. This study aimed to determine the risk factors for nephrotoxicity in neonates receiving vancomycin to promote the safe use of vancomycin.</p> Methods <p>We searched international and Chinese databases from 1990 to 24 March 2024 for studies involving neonates receiving vancomycin and reporting their nephrotoxic outcomes. Effects were estimated with 95% confidence intervals (CIs), odds ratios (ORs), and standardized mean differences. We evaluated the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool.</p> Results <p>In total, the study included 12 retrospective cohort studies involving 2079 neonates. In neonates receiving vancomycin, the incidence of nephrotoxicity varied from 2.7 to 20.0%. Moderate-quality evidence indicated that furosemide (OR 5.80; 95% CI 2.98–11.28), amphotericin B (OR 2.75; 95% CI 1.23–6.12), patent ductus arteriosus (OR 5.93; 95% CI 2.80–12.55), and necrotizing enterocolitis (OR 4.49; 95% CI 2.12–9.49) were risk factors for nephrotoxicity in neonates receiving vancomycin. Low-quality evidence suggested that vasoactive agents (OR 9.23; 95% CI 1.06–80.62) were risk factors. Subgroup analysis with moderate-quality evidence identified a steady-state vancomycin trough concentration &gt; 20 mg·L⁻¹ (OR 6.87; 95% CI 3.81–12.39) as a risk factor. Very low-quality evidence indicated that aminoglycosides (OR 0.29; 95% CI 0.13–0.62) were not risk factors.</p> Conclusions <p>This study reveals the nephrotoxic risk factors for neonates receiving vancomycin, which could help in the implementation of measures to prevent further renal impairment.</p> PROSPERO Registration Number <p>CRD42024564584.</p> Graphical Abstract <p></p>