Major depressive disorder (MDD) is a global public health concern and the leading cause of disability worldwide. It severely impairs cognitive, emotional, and social functioning, and is associated with attention, memory, and executive function deficits. MDD was traditionally considered as a neuropsychiatric disorder focused on neuronal dysfunction; however, growing evidence recognizes glial cells, particularly astrocytes, as crucial cells for the pathophysiology and pathogenesis of MDD. Astrocytes play essential roles in the central nervous system, including neurotransmitter uptake, metabolic support, neurotrophic factor production, and synaptic regulation. Evidence from MDD human patients, as well as studies involving animal models have revealed the astrocytic dysfunction as a critical factor in the pathophysiology of MDD, pointing to widespread alterations in astrocyte density, morphology, and function. This review summarizes current knowledge regarding astrocytes and MDD and discuss the potential of targeting astrocytes as a novel avenue for antidepressant development.