Abstract: Anti-seizure medications (ASMs) represent the pillar of the treatment of epilepsy. The rate of drug-resistant epilepsy remained substantially unchanged over time and there is still the need for new and more effective treatment options. Brivaracetam, cenobamate, eslicarbazepine acetate, lacosamide and perampanel are ‘third-generation’ ASMs. The aim of this article is to summarize the currently available evidence about the relative efficacy and tolerability of the ‘third-generation’ ASMs as adjunctive treatment of focal-onset seizures in adults. So far, no randomized controlled study directly compared these ASMs, and their comparative efficacy and tolerability have been indirectly evaluated by one network meta-analysis. Sixteen trials were included in the network meta-analysis. The efficacy endpoints were the rates of seizure response and seizure freedom, defined as ≥ 50% and 100% reduction in baseline monthly seizure frequency. The tolerability endpoints were the rate of patients who developed any treatment emergent adverse events (TEAEs) and any TEAE leading to drug discontinuation. Cenobamate had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction. Brivaracetam and lacosamide had the greatest likelihood to rank as the best-tolerated treatments for the occurrence of any TEAE and TEAE leading to discontinuation. Although network meta-analyses are not substitutes of direct comparisons, they can provide valuable evidence about the hierarchy of interventions. Additional real-world data can be useful complement to characterize the clinical profile and therapeutic potentialities of third-generation ASMs.