Homocysteine is a sulfur-containing amino acid, which is derived from demethylation of methionine. Current evidences have shown that elevated serum levels of homocysteine can lead to migraine, and exacerbate the severity and frequency of migraine attacks. Some investigations have indicated that vitamin supplementations with vitamin B₆, B₉ and B₁₂ can decrease serum levels of homocysteine, and be effective in alleviating of severity and frequency of migraine attacks. So, this study aimed to review evidences on association of serum homocysteine levels with migraine and effects of vitamin supplementations with vitamin B₆, B₉ and B₁₂ on it. This review was done by searching on PubMed, Scopus, Science Direct and Web of Science by entering migraine, headache, homocysteine, vitamin B₆, vitamin B₉, folic acid and “vitamin B₁₂ as keywords. In this study, clinical trial, cross-sectional, retrospective and prospective studies which were published during 2000 to 2015 were reviewed. We included studies that were diagnosed migraine based on international headache society criteria and were done on human, and excluded non-English language articles and studies that investigated pulsating headaches as the main aim. In most evaluated studies, homocysteine levels were significantly higher in patients with migraine, especially migraine with aura, compared to control group and healthy subjects. Vitamin supplementations with B₆, B₉ and B₁₂ decreased the homocysteine levels, severity attacks and its related disabilities; however, results on frequency of migraine attacks were inconsistent. Based on results, it seems that low levels of homocysteine with vitamin supplementations with B₆, B₉ and B₁₂ can decrease severity and disabilities of migraine, although more studies are suggested due to few studies in this regard.