Objective To systematically review the efficacy and safety of non-ergoline dopamine agonists (pramipexole, ropinirole, and rotigotine) and α2δ ligands (pregabalin and gabapentin-enacarbil) in the treatment of restless legs syndrome (RLS). Methods The PubMed, EMbase, The Cochrane Library, CBM, WanFang Data, and CNKI databases were electronically searched for randomized controlled trials (RCTs) assessing different medications for RLS from 2000 to 2021. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. The network meta-analysis was then performed using Stata 16.0 software and R 4.1.0 software. Results A total of 36 RCTs involving 7 666 patients were included. The results of the network meta-analysis showed that gabapentin-enacarbil decreased IRLS scores to the greatest extent among all drugs (MD=−6.42, 95%CI −8.8 to −4.16), was superior to pramipexole (MD=−3.27, 95%CI −6.54 to −0.15), and was associated with the highest CGI-I response rates (RR=1.73, 95%CI 1.52 to 2.00). In terms of tolerance and safety, patients receiving rotigotine presented an increased incidence of withdrawal due to adverse events. Ropinirole had the highest incidence of nausea. Headache was most common side effect in rotigotine, while the incidences of somnolence and dizziness were higher in gabapentin-enacarbil than other treatments. Conclusion Current evidence suggests that gabapentin-enacarbil may be the best treatment for RLS. Rotigotine is associated with the worst tolerance. For safety, nausea is most common in ropinirole, headache is most common for rotigotine, and patients receiving gabapentin-enacarbil show increased incidences of somnolence and dizziness.