Objective. To evaluate the efficacy and safety of Chuanxiong Qingnao Granule (CQG) to treat migraine. Method This study was a randomized, double-blind, placebo-controlled trial. All migraineurs were recruited and randomly assigned into a treatment group treated with CQG and a control group treated with a placebo The whole research process included a 4-week baseline, 12-week intervention, and 12-week follow-up The primary outcome was responder rate, defined as the percentage of migraineurs with 50% or more reduction in the frequency of migraine attack during treatment and posttreatment period compared with the baseline The secondary outcomes were the number of migraine days, migraine attack frequency, visual analogue scale (VAS), Fatigue Severity Scale (FSS), Hamilton Depression Scale (HAMD), and Migraine Disability Assessment (MIDAS). Results. A total of 346 migraineurs completed the research and were included in the intention-treatment analyses The response rates differed significantly between the treatment group and the control group (71.5% vs. 12.1% at week 12 and 83.1% vs. 3.4% at week 24). Attack frequency, days of headache attack, VAS, FSS, HAMD, and MIDAS decreased at week 12 in both groups with more reduction in the treatment group (P < 0.001). No severe adverse events were observed in this trial. Conclusion. Chuanxiong Qingnao Granule can significantly improve headache symptoms in patients with migraine while improving disability, fatigue, and depression with a good safety profile.