Objectives: Depression is increasingly recognized as a disorder involving systemic metabolic dysregulation and gut brain axis imbalance. This study investigated whether acupuncture, as a means of activating the body’s “invisible network,” can restore systemic metabolism and gut microbiota in a depression mouse model. Methods: We induced depression in male C57BL/6 mice and conducted untargeted UHPLC–MS metabolomics and gut microbiome sequencing to evaluate systemic changes associated with acupuncture treatment. Results: Depression caused pronounced metabolic disturbances, including alterations in neurotransmitter metabolism, increased oxidative stress, and impaired energy metabolism. It was also accompanied by significant shifts in gut microbiota composition, characterized by enrichment of hormone-related and inflammation-associated taxa. Acupuncture treatment partially restored both metabolic and microbial profiles. Notably, acupuncture modulated lipid metabolism across multiple organs and altered stress hormone–related metabolic pathways, which were closely linked to changes in gut microbiota. Conclusion: By awakening the body’s invisible network, acupuncture may counteract depression through coordinated modulation of systemic metabolism and gut microbiota, offering a promising gut–brain axis–based therapeutic strategy.