Background: Concurrent use of valproate and carbapenem antibiotics may decrease serum valproate concentration (SVC). This study evaluated the effects of carbapenem–valproate drug interactions. Research design and methods: We screened PubMed, EMBASE, and Cochrane databases for eligible prospective or retrospective studies that evaluated the effect of concurrent use of carbapenem and valproate compared with valproate alone on SVC. Primary outcomes were the change in SVC from before the addition of the carbapenem to the SVC during the use of carbapenems and after carbapenem discontinuation, and seizure-related outcomes. Secondary outcomes were the influence of valproate or carbapenem dose on SVC and Drug Interaction Probability Scale scores. Results: Twelve studies (633 patients) were included. Compared with valproate alone, combination treatment with carbapenem substantially decreased mean SVC (mean difference, −43.98 mg/L; 95% confidence interval, −48.18 to −39.78). The onset of SVC decreases was within 1–3 days following carbapenem initiation. Seizure frequency increased by 26.3% during combination treatment. No difference was found in mean SVC between the different doses of valproate or carbapenem during combination treatment. Mean SVC increased to similar pre-carbapenem level within 1 to 2 weeks after carbapenem discontinuation. Conclusions: The drug interaction between valproate and carbapenem causes substantial SVC decreases, even to subtherapeutic levels, which may increase the risk of seizures.