Objective To systematically evaluate the efficacy and safety of flupentixol and melitracen combined with flunarizine for preventing and treating migraine.Methods Controlled clinical trials from Embase, PubMed, and Cochrane Library, CNKI, VIP, and Wanfang Data were searched, and randomized controlled trials (RCTs) of flupentixol and melitracen combined with flunarizine for preventing and treating migraine were included. The quality of the included studies was assessed by Cochrane systematic reviews, and a meta-analysis was carried out on the included studies with RevMan 5.1 software. Results Ten studies were included, involving 932 patients. Meta-analysis showed that there was a significant difference between the group using flupentixol and melitracen combined with flunarizine and the group using flunarizine alone for migraine [OR=4.23, 95%CI (2.90, 6.17), P<0.00001]. The adverse events of the two groups showed no significant differences [OR=1.14, 95%CI (0.58, 2.26), P=0.70]. Conclusions Limited studies show that flupentixol and melitracen combined with flunarizine has better efficacy compared with using flunarizine alone, and the safety is satisfactory as well. However, the included studies is limited in quantity and poor in quality, and therefore multi-centered and large-scale RCTs with rational design and strict execution are needed to validate its efficacy and safety.