Epilepsy, a heterogeneous neurological disorder, has long been challenging to treat. Recent advances in gut-brain axis research have uncovered significant roles for gut microbiota in the onset, progression, and treatment of epilepsy. Dysbiosis of the gut microbiota has been linked to epilepsy, with alterations in microbial diversity affecting seizure susceptibility and treatment responses. Interventions targeting the microbiota, such as probiotics, fecal microbiota transplantation, and ketogenic diet, have shown promise in animal models and clinical studies. However, the precise molecular mechanisms underlying these interventions and their interaction with antiepileptic drugs remain poorly understood. This review synthesizes the latest evidence on the gut-brain axis and its implications for epilepsy, reviews the paradigm shift driven by spatial multi-omics technologies, and discusses the regulatory and ethical dilemmas surrounding microbial-based therapies. Finally, we propose future research directions that integrate multi-omics approaches to deepen our understanding of the gut-brain interaction and optimize microbiota-based treatments for epilepsy.