Over the past few years, research has suggested a link between valproate sodium (VPA) therapy and weight gain. This systematic review investigates the association between obesity and VPA treatment in epilepsy patients. PubMed, Web of Science, Science Direct, EBSCO, SCOPUS, Wiley, and Cochrane Library were used to perform a systematic literature search. Study articles were screened by title and abstract using Rayyan QCRI then a full-text assessment was implemented. A total of nine studies with 416 patients were included. Valproate-treated adult patients for epilepsy experience weight gain up to obesity while undergoing treatment. Studies investigating the pediatric population reported that obesity in children receiving VPA is widespread. Treatment with VPA is associated with significant weight gain and related metabolic disorders in adults and children with epilepsy. Leptin and insulin resistance are suggested as the primary mechanisms underlying weight gain with VPA, despite the need for extensive research into the mechanisms underlying their development in patients taking the medication.