To further investigate the effects of geniposide on depression, we treated CUMS mice with geniposide. Intriguingly, our results manifested a significant decrease of the contents of IL-1β, IL-6, TNF-α, and TGF-β, and expression of phosphorylated SMAD2/3, phosphorylated NF-κB, phosphorylated ERK1/2, and phosphorylated JNK in frontal cortex tissues. Here, SMAD2 is linked to depressive disorder.