Epilepsy is a devastating neurological condition that affects over 70 million people worldwide. Apart from idiopathic epilepsy, numerous diseases have been reported to cause secondary epilepsy. Polyphenols, ubiquitously existing in fruits and vegetables, has become a promising neuroprotective candidate against multiple neurological abnormalities due to its interplay with gut microbiome composed of the bacterial population in gastrointestinal system. This bioactive compound is also being tested for the management of epileptogenesis. However, there is still insufficient evidence from mechanistic studies to demonstrate the causal relationship between anti-epileptic effect of polyphenols and microbial alteration. In this review, we provide the brief overview of epilepsy, polyphenols and gut microbiota. We then analysis the association of polyphenols and gut microbiota particularly in the epilepsy and symptomatic seizures-induced by epilepsyrelated disorders. We also discuss the possibility for the combined application with probiotics to improve the bioavailability and bioaccessibility of polyphenols for expanding its anti-epileptic function. We finally summarize the therapeutic potential of anti-seizure polyphenols through affecting gut microbiome, and propose that the anti-epileptic effect of polyphenols may be tightly relevant to intestinal bacterial flora for overcoming epilepsy and its comorbidities simultaneously. Therefore, the dietary polyphenols targeting specific bacteria may achieve the outcome of ‘one stone, two birds’.