Physiologic changes due to aging, pregnancy, nutritional status, drug interactions, and can affect pharmacokinetics and pharmacodynamics of antiepileptic drugs. In this review article, the interactions between phenytoin and herbs recorded in the literature were summarized according to the Medline database (via PubMed). Our results revealed that, changes in phenytoin's bioavailability were reported for co-administration of herbs or herbal extracts. An increase in phenytoin blood levels was established with Piper nigrum, Mentat, and Lipidum sativum in in vitro and/or in vivo studies. In contrast, herbphenytoin interactions led to sub-therapeutic levels of phenytoin in other cases with herbs such as Cannabis, Ginkgo biloba, Morinda citrifolia, Nigella sativa, and Trigonella foenum graceum. In addition, the findings of other pharmcodynamic experiments showed that various herbs, including Zizyphus jujube, Terminalia chebula, Curcuma longa L, and Centella asiatica, improved the pharmacological impact of phenytoin. To reduce the patients' health risks, health professionals involved in their treatment are expected to be thoroughly educated about the interactions between phenytoin and medicinal plants.