Abstract Objective To assess the efficacy of cannabis for the treatment of acute migraine. Background Preclinical and retrospective studies suggest cannabinoids may be effective in migraine treatment. However, there have been no randomized clinical trials examining the efficacy of cannabinoids for acute migraine. Methods In this randomized, double‐blind, placebo‐controlled, crossover trial, adults with migraine treated up to four separate migraine attacks, one each with vaporized (1) 6% Δ9‐tetrahydrocannabinol (THC) (THC‐dominant), (2) 11% cannabidiol (CBD) (CBD‐dominant), (3) 6% THC + 11% CBD, and (4) placebo cannabis flower in a randomized order. Washout period between treated migraine attacks was ≥1 week. The primary endpoint was pain relief, and secondary endpoints were pain freedom and most bothersome symptom freedom, all assessed at 2‐h post‐vaporization. Results Ninety‐two participants were enrolled and randomized, and 247 migraine attacks were treated. THC + CBD was superior to placebo at achieving pain relief (67.2% vs. 46.6%, odds ratio [95% confidence interval] 2.85 [1.22, 6.65], p = 0.016), pain freedom (34.5% vs. 15.5%, 3.30 [1.24, 8.80], p = 0.017), and most bothersome symptom freedom (60.3% vs. 34.5%, 3.32 [1.45, 7.64], p = 0.005) at 2 h, as well as sustained pain freedom at 24 h and sustained most bothersome symptom freedom at 24 and 48 h. THC‐dominant was superior to placebo for pain relief (68.9% vs. 46.6%, 3.14 [1.35, 7.30], p = 0.008) but not pain freedom or most bothersome symptom freedom at 2 h. CBD‐dominant was not superior to placebo for pain relief, pain freedom, or most bothersome symptom freedom at 2 h. There were no serious adverse events. Conclusion Acute migraine treatment with 6% THC + 11% CBD was superior to placebo at 2‐h post‐treatment with sustained benefits at 24 and 48 h.