© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Depression is the leading cause of disability worldwide with global distribution of 322 million people suffering from the disease. While much is understood about depression, the underlying pathophysiology is yet to be fully characterized. Recently, the unfolded protein response (UPR) has been shown to be involved in regulating key aspects like inflammation, cell death, and behavioral depression. The UPR is an evolutionarily conserved ancient response system that reacts to the stressful environmental impact on a cell; the net effect of stress to a cell is that the quality of protein folding is diminished. The UPR responds by repairing and removing misfolded proteins and, if necessary, initiates apoptosis. Here, we demonstrate that the UPR is not only involved in depression, but that its activation causes a depressive phenotype. The hippocampi of rats were directly infused with 500 ng of tunicamycin (TM), an agent that initiates the UPR by blocking N-terminal glycosylation. Three to 8 days post-surgery, the rats showed depressive behavior in escape latency, forced swim despair, sucrose preference anhedonia, and also physiological signs of depression like decreased weight. Further, these behavioral changes were associated with enhanced expression of key UPR genes and proteins in the hippocampus. We propose that this model will make an excellent tool for studying depression and for understanding pathways that are affected by the UPR which directly causes depressive behavior.