Depression has a complex origin that involves genetic, neurophysiological, hormonal, psychosocial, and environmental factors. There is a possible relationship between vitamin B12 deficiency and depression, with evidence that supplementation may alleviate symptoms in adults treated with selective serotonin reuptake inhibitors. Although this association has been found, a direct causal relationship has yet to be established, which requires more rigorous research. This article reviews and synthesizes the available evidence on this relationship and its clinical implications. More studies are needed to confirm the association and detection in at- risk populations.