Depression is the most common chronic mental illness and is characterized by low mood, insomnia, and affective disorders. However, its pathologic mechanisms remain unclear. Numerous studies have suggested that the ghrelin/GHSR system may be involved in the pathophysiologic process of depression. Ghrelin plays a dual role in experimental animals, increasing depressed behavior and decreasing anxiety. By combining several neuropeptides and traditional neurotransmitter systems to construct neural networks, this hormone modifies signals connected to depression. The present review focuses on the role of ghrelin in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. Furthermore, ghrelin/GHSR can activate multiple signaling pathways, including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK, to produce antidepressant effects, given which it is expected to become a potential therapeutic target for the treatment of depression.