Abstract: Traditional anti-depressant therapy based on the regulation of monoamine neurotransmitters has shown certain limitations. Recently, accumulating clinical and preclinical studies have reported the tantalizing link between immune dysregulation, inflammatory process and the initiation and exacerbation of major depressive disorder (MDD). With a deepening understanding of neural-immune-metabolic interactions, an immunometabolism driven disease network has attracted huge interests in understanding neuronal inflammation and dysfunction underlying MDD pathogenesis and intervention. This review describes recent data uncovering immunometabolic dysregulation as a key factor in MDD network, with a focus on the recent appreciation of immune-metabolic actions of several anti-depressant compounds. The implications for the discovery of novel antidepressant drugs and clinical management of MDD are discussed.