Aim: To implement pharmacokinetic drug monitoring and individualize the posology of new antiepileptic drugs, the first HPLC-diode array detection method was developed and validated to simultaneously quantify lacosamide, levetiracetam and zonisamide in human plasma. Materials & methods: Preceded by a reproducible liquid–liquid extraction, chromatographic separation was achieved by using a C18 column of 5 cm length and a mobile phase of water/acetonitrile. Full validation was performed according to international guidelines. Results: The method was linear within 0.5–30, 2.5–40.0 and 0.5–50.0 μg ml-1 for lacosamide, levetiracetam and zonisamide, respectively (r2 ≥ 0.998), accurate (-12.411–8.303%), precise (≤8.875%). Conclusion: This innovative HPLC-diode array detection method was successfully employed in clinical practice and is expected to empower epileptic patients with a personalized pharmacotherapy service.