Depression is one of the world’s serious health problems with high prevalence, high disability and high recurrence rate, and places a great burden on society. The newly discovered CREB-regulated transcription coactivator 1 (CRTC1) is highly expressed in the brain, especially in hippocampal neurons, and plays an important role in dendrite growth, long-term synaptic plasticity and behavior. Since Crtc1 knockout (Crtc1^-/-) mice were first successfully prepared in 2012 and Crtc1^-/- mice exhibited a depression-like behavioral phenotype, the growing clues suggest that CRTC1 is involved in depression. Our previous work demonstrates that knockdown of CRTC1 in hippocampal dentate gyrus directly induced depression-like behavior in mice. Downregulation of CRTC1 expression in hippocampus is associated with depression-like behaviors in CUMS (chronic unpredictabk mild stress), CSDS (chronic social defeat stress) and CRS (chronic restrain stress) mouse models, LPS(lipopolysaccharide)-treated mouse model and prenatal stress-induced depression model in offspring rats. Furthermore, abnormal CRTC1 expression or activation may be involved in depression-like behavior via SIK2/CRTC1/CREB/BDNF pathway, CRTC1/BDNF/TrkB/VGF pathway, agmatinergic system and neuroinflammation. In addition, Crtc1^-/- mice are shown to be resistant to the antidepressant effects of the tricyclic antidepressants such as fluoxetine, desipramine, venlafaxine and imipramine etc., suggesting that CRTC1 alterations may be related with treatment-resistant depression. Histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) partially rescues the depression-like behavior of Crtc1^-/- mice accompanied by an increased expression of BDNF, the effects are mediated by CRTC1. Although CRTC1 expression is disturbed in the brain of depression-related models, whether and how it is involved in the process of neurogenesis and neuroplasticity impairments in depression still needs further research. This article reviews the research of CRTC1 in depression from the aspects of behavior, related signal pathways and participation in the role of antidepressants.