ObjectiveTo systematically review the efficacy and safety of second-line medications for status epilepticus (SE). MethodsThe Cochrane Library, PubMed, EMbase, CNKI, CBM, and WanFang Data databases were electronically searched to collect randomized controlled trials (RCTs) of second-line medications for SE from inception to May, 2021. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Network meta-analysis was then performed using Stata 15.1 software and R 4.1.0 software. ResultsA total of 23 RCTs were included and 4 regimens were involved: levetiracetam (LEV), phenytoin/fosphenytoin (PHT), valproate (VPA), and phenobarbital (PHB). The results of network meta-analysis showed SE control rate validity sorting to be PHB>LEV>VPA>PHT, the epilepsy recurrence rate in 24 hour validity sorting to be VPA>PHB>LEV>PHT, those requiring further antiepileptic drug treatment rate validity sorting to be LEV>PHT>VPA, and drug safety security sorting to be VPA>LEV>PHT>PHB. Subgroup analysis showed PHB was optimal for SE control in children and adults, VPA had the optimal effect on other efficacy indicators in children, LEV was the safest in children and elderly patients, and VPA was the safest in adults. ConclusionsCurrent evidence suggests that PHB is the optimal for SE control, however, the safety is unsatisfactory; VPA and LEV have their own advantages in the treatment of SE, and their safety is satisfactory. VPA is recommended for adult patients, and LEV is recommended for children and elderly patients.