Depression is a kind of severe mental illness that seriously endangers human physical and mental health， and its pathophysiological mechanism is extremely complex. The antidepressant effect of SIRT1 （Sirtuin 1， Silent Information Regulator Factor 2-related enzyme I） has been widely demonstrated， but its mechanism is still unclear. The regulatory role of miR-124 has also been found to be important in the onset of depression. The purpose of this paper is to introduce how SIRT1 regulates miR-124， alleviates the pathological changes of hypothalamic-pituitary-adrenal axis（ HPA axis） hyperfunction and neurotrophic factor deficiency， exerts antidepressant function. The elucidation of this mechanism could provide important clues for depression pathogenesis research and drug development.