The incidence of depression has been rising rapidly, and depression has been recognized as one of the world’s leading causes of disability. More recently, depression has been associated with an increased risk of symptomatic atherosclerotic disease as well as worse perioperative outcomes in patients with cardiovascular disease. Additionally, recent studies have demonstrated an association between depression and peripheral artery disease (PAD), which has been estimated to affect more than 200 million people worldwide. These studies have identified that depression is associated with poor functional and surgical outcomes in patients with PAD. Although the directionality and specific mechanisms underlying this association have yet to be clearly defined, several biologic and behavioral risk factors have been identified to play a role in this relationship. These factors include tobacco use, physical inactivity, medical non-adherence, endothelial and coagulation dysfunction, and dysregulation of the hypothalamic-pituitary-adrenal axis, autonomic system, and immune system. In this article, we review these potential mechanisms and the current evidence linking depression and PAD, as well as future directions for research and interventional strategies. Understanding and elucidating this relationship may assist in preventing the development of PAD and may improve the care that patients with PAD and comorbid depression receive.