Depression is a major cause of disability and has adverse effects. Despite the many types of antidepressants, clinical treatments of depression remain poor. Therefore, novel anti-depressant mechanisms need to be explored. The beneficial effects of irisin on the nervous system are gradually being elucidated, and studies have found that irisin has an anti-depressant effect, which may become a new treatment for depression. This study explored the mechanism of irisin and its upstream and downstream anti-depressants by reviewing the existing studies explaining the link between irisin and depression, and proposes that SIRT1/ PGC-1α may mediate FNDC5/ irisin to regulate BDNF to promote neurogenesis and improve depression, which provides a new idea to study irisin and its upstream and downstream antidepressants.