Our multifaceted approach involving chemogenetic overexpression of hippocampal HO-1, pharmacological administration of CO-rich saline, or CO gas in the absence or presence of LPS administration–blunted depression- and anxiety-like symptoms, as demonstrated in the battery of behavioral tests such as SPT, FST, TST, and OFT, and suggests that the HO-1/CO system might be a new therapeutic target in the treatment of depression. This evidence concerns the gene HMOX1 and major depressive disorder.