Seizures are common in neonates with moderate and severe hypoxic ischemic encephalopathy (HIE) and are associated with worse outcomes, independent of HIE severity. In contrast to adults and older children, no new drugs have been licensed for treatment of neonatal seizures over the last 50 years, because of a lack of controlled clinical trials. Hence, many antiseizure medications licensed in older children and adults are used off-label for neonatal seizure, which is associated with potential risks of adverse effects during a period when the brain is particularly vulnerable. Phenobarbital is worldwide the first-line drug and is considered standard of care, although there is a limited evidence base for its efficacy. Second-line agents include phenytoin, benzodiazepines, levetiracetam, and lidocaine. These drugs are discussed in more detail along with two emerging drugs (bumetanide and topiramate). More safety, pharmacokinetic, and efficacy data are needed from well-designed clinical trials to develop safe and effective antiseizure regimes for the treatment of neonatal seizures in HIE.