Introduction - Therapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED). The aim of this phase II trial is to determine the benefits of LEV by applying a strict methodology and to estimate the optimal dose of LEV as a first-line AED to treat seizures in newborns suffering from hypoxic-ischaemic encephalopathy.Methods and analysis - LEVNEONAT-1 is an open and sequential LEV dose-finding study. The optimal dose is that which is estimated to be associated with a toxicity not exceeding 10% and an efficacy higher than 60%. Efficacy is defined by a seizure burden reduction of 80% after the loading dose. Four increasing dose regimens will be assessed including one loading dose of 30, 40, 50 or 60 mg/kg followed by eight maintenance doses (ie, a quarter of the loading dose) injected every 8 hours. A two-patient cohort will be necessary at each dose level to consider an upper dose level assignment. The maximal sample size expected is 50 participants with a minimum of 24 patients or fewer in the case of a high rate of toxicity. Patients will be recruited in five neonatal intensive care units beginning in October 2017 and continuing for 2 years. In parallel, the LEV pharmacokinetics will be measured five times (ie, 30 min; 4 and 7 hours after the loading dose; 1-3 hours and 12-18 hours after the last maintenance dose).Ethics and dissemination - Ethics approval has been obtained from the regional ethical committee (2016-R25) and the French Drug Safety Agency (160652A-31). The results will be published in a peer-reviewed journal. The results will also be presented at medical meetings. Trial registration number - NCT02229123; Pre-results.