This study was proposed to compare the relative efficacy and tolerability of the second and third generation AEDs for refractory epilepsy. The 50% responder rate (RR) was selected as the efficacy outcome whereas the incidence of dizziness and somnolence were considered to evaluate the tolerability of AEDs. Odds ratio (OR) and their 95% credible interval (CrI) were obtained using a consistency model and surface under the cumulative ranking curve (SUCRA) value was calculated to rank AEDs. Topiramate appeared to be significantly more effective than placebo, eslicarbazepine acetate, perampanel, pregabalin, zonisamide, gabapentin and lamotrigine with respect to the 50% RR (all OR > 1). Patients who were managed by eslicarbazepine acetate, perampanel, oxcarbazepine, topiramate and pregabalin were more likely to suffer from dizziness compared to those who receive placebo (all OR > 1). Perampanel, topiramate and pregabalin were related to elevated risks of somnolence compared to placebo (all OR > 1). Moreover, topiramate ranked highest with respect to 50% RR (SUCRA = 0.968) whereas levetiracetam appeared to have balanced efficacy and tolerability (SUCRA = 0.769, 0.743, 0.604 and 0.659). In conclusion, topiramate was the most efficacious AED, while levetiracetam was able to provide patients with balanced efficacy and tolerability.