Yueju, a Chinese traditional herbal medicine formula, has a rapid antidepressant action. We have previously identified two active ingredients from Yueju: two iridoids, geniposide (GM) and shanzhiside methyl ester (SM). Only co-treatment (GS) with GM (44 mg/kg) and SM (4.7 mg.kg) elicits synergistic rapid antidepressant action by activating polypeptide (PACAP) activity and its associated CaMKII–BDNF signalling the hippocampus. We further investigate whether chronic treatment with GM and SM are effective in eliciting antidepressant effects via enhancing hippocampal adult neurogenesis. Two mouse models of depression including 4-week chronic unpredictable stress and diabetes model induced by 8-week high fat diets were used. Adult c57/BL6J male mice were subjected to vehicle, or co-treatment with low (GP 11mg/kg + SM 0.2 mg/kg) or high (44mg/kg + SM 4.7 mg/kg) dose of GS for two weeks in stress model and four weeks in diabetic model, respectively. Antidepressant effects were evaluated using various behavioral experiments. Hippocampal adult neurogenesis was examined using immunostaining. Our results found that high dose GS significantly reduced depression/anxiety-like behavior in novelty object recognition and tail suspension test independent to changes of hippocampal neurogenesis in stressed mice, whereas high dose GS reduced depression/anxiety-like behavior in forced swim test, and elevated plus maze in an association with enhanced hippocampal cell proliferation. Our results have suggested that chronic treatment with GS co-treatment had antidepressant effects in two mice models, though their effects on hippocampal adult neurogenesis are different.