The development of depression frequently impacts epileptic patients due to unmanaged central nervous system changes. This may severely reduce their quality of life. These mental conditions can lead to the administration of illicit drugs for self-medication. However, these substances may increase seizure frequency. The combination of this condition may both interacting brain disorders deeply aggravate each other, requiring simultaneous, comprehensive treatment. The aim will be to systematically evaluate the role of phytomedicine in managing comorbid depression and recreational substance use in people with epilepsy. The methods followed the PRISMA guidelines. This systematic review protocol outlines an evaluation of phytomedicine’s role in managing comorbid depression and recreational substance use in epilepsy patients. Data were searched using nine online databases for 2000–2026 primary studies, extracted data, assessed risk of bias, and performed a narrative or meta-analysis synthesis. It is well documented that depression and recreational substance use frequently coexist, with severity influenced by youth, homelessness, unemployment, childhood trauma, and prolonged substance dependence. Several evidence globally consistently demonstrates strong associations between depressive symptoms and heroin, cocaine, benzodiazepine, and alcohol use. The statistical analyses obtained indicate that substance use and depression reinforce each other, highlighting the need for integrated mental health, addiction, and psychosocial interventions to improve clinical outcomes. This highlighted a complex interaction among depression, epilepsy, and substance use. It emphasised an integrated management approach while cautiously evaluating phytomedicine’s efficacy, safety, and drug interactions. Therefore, the use of phytomedicine may complement integrated epilepsy care by addressing depression and substance use, although robust clinical evidence remains essential for validation.