This study aimed to evaluate a microemulsion system (ME) containing phenobarbital in epilepsy model induced by pilocarpine in rats and to oxidative stress and histologic lesions in hippocampus. The microemulsion was applied to the shaved back of Wistar rats. The animals were divided into the following groups: control group (P400); ME50 40 mg/kg, topically-t.p.; ME100, 40 mg/kg, t.p.; EM50, 40 mg/kg, t.p.; phenobarbital solution 40 mg/kg (PS), oral. After 60 min, behavioral changes were evaluated for 1 h in the model of epileptical crisis induced by pilocarpine. Phenobarbital in microemulsion was able to increase the latency for status epilepticus (SE) (p < 0.05), decrease the number of epileptical crisis (ME50: p < 0.001; ME100: p < 0.01) and decrease mortality rate by 80% compared to P400. In EM50 and PS groups, deaths were decreased by 53.3% and 100% respectively. The ME50 and ME100 groups were able to reduce oxidative stress in experimental animals when compared to the P400. The microemulsion was still capable of reducing neuronal damage in the hippocampal areas. The results of this study come in an innovative way, demonstrating the ability of transdermal ME50 and ME100 to reduce pilocarpine-induced epileptical crisis, oxidative stress, besides neuronal damages.