Major depressive disorder (MDD) is a debilitating and widespread illness that exerts significant personal and socioeconomic consequences. Recent genetic and brain-imaging studies suggest that bicaudal C homolog 1 gene (BICC1), which codes for an RNA-binding protein, may be associated with depression. Here, we show that BICC1 mRNA is upregulated in the dorsolateral prefrontal cortex and dentate gyrus of human postmortem MDD patients. We also show that BICC1 is increased in the prefrontal cortex and hippocampus in the rat chronic unpredictable stress (CUS) model of depression. In addition, we show in vivo that a single acute antidepressant dose of ketamine leads to a rapid decrease of BICC1 mRNA, while in vitro, we show that this is likely due to neuronal activity-induced downregulation of BICC1. Finally, we show that BICC1 knockdown in the hippocampus protects rats from CUS-induced anhedonia. Taken together, these findings identify a role for increased levels of BICC1 in the pathophysiology of depressive behavior.