Aims: The aim of this study was to elucidate the risk factors associated with the development of cefepime-induced neurotoxicity (CIN). Methods: This systematic review utilized keywords “cefepime” and “neurotoxicity”, sourced from PubMed, Scopus, Web of Science and Google Scholar. Meta-analysis was conducted using a random effects model utilizing Mantel–Haenszel and inverse variance analysis for dichotomous and continuous outcomes, respectively. Results: Analysis of 23 articles revealed that estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 is the primary factor in CIN, with an odds ratio of 10.06 (95% confidence interval [CI] = 5.05–20.03, P < 0.0001). Other significant factors include central nervous system (CNS) abnormalities, age, body weight, albumin levels, diabetes mellitus, hypertension, chronic lung disease and inappropriate dosing. Subgroup analysis of continuous cefepime infusion utilization, based on several risk factors, indicated a lower odds ratio in comparison to intermittent infusion. For cefepime therapeutic drug monitoring (TDM) to determine potential CIN cases, the proposed trough concentration (Ctrough) threshold for intermittent infusion is 20 mg/L, while the steady-state concentration (Css) threshold for continuous infusion is 63 mg/L. Conclusions: Numerous risk factors are significantly associated with CIN, with renal impairment being the most significant. Continuous cefepime infusion is a potential strategy to mitigate CIN, in addition to dose adjustment and TDM. © 2025 British Pharmacological Society.