Depression is a prevalent mental disorder with limited effective treatments, posing a significant global issue. This study explored L-theanine and geniposide, key components in “food-medicine homology” materials, to determine if their combination (TG) could alleviate depression-like behaviors and hippocampal neuronal damage in a chronic unpredictable mild stress (CUMS) mouse model. Male C57BL/6J mice were divided into control, CUMS model, and CUMS + TG groups with varying doses. The CUMS group displayed depression-like behaviors, including reduced activity and sucrose preference. TG treatment partially reversed these changes, significantly increasing antioxidant enzyme activities, decreasing pro-inflammatory cytokine levels, and improving neuromodulator levels. RNA-seq analysis identified the transthyretin (TTR) gene, upregulated in the model group but downregulated after TG treatment. TG treatment modulated intestinal microbiota composition compared to the CUMS group, including increased Firmicutes, reduced Bacteroidetes and Prevotella, and variable changes in Bifidobacterium abundance. In conclusion, our study indicates that CUMS exposure upregulates stress hormones and TTR expression, associated with neuroinflammation, oxidative stress, monoamine depletion, depression-like behaviors, and intestinal microbiota dysbiosis. TG treatment alleviates these effects and modulates intestinal microbiota, suggesting L-theanine and geniposide’s potential as a novel depression therapy.