<p>The understanding of Major Depressive Disorder (MDD) has evolved beyond the classic monoamine hypothesis to include significant immune-inflammatory and metabolic dysfunction. At the intersection of these systems, adiponectin (APN), an adipokine with potent anti-inflammatory, insulin-sensitizing, and neuroprotective properties, has emerged as a key molecular link. Clinical evidence reveals a complex association, where hypoadiponectinemia is most consistent in medication-naïve MDD patients with metabolic comorbidities, though this relationship is confounded by antidepressant use and clinical heterogeneity. By contrast, preclinical studies robustly demonstrate that adiponectin signaling exerts antidepressant-like effects by modulating hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, reducing neuroinflammation, and promoting hippocampal neurogenesis. This review critically synthesizes this evidence, exploring paradoxical findings that underscore a context-dependent role for adiponectin. We also assess the translational potential of this knowledge, evaluating how antidepressants modulate its signaling and discussing promising adiponectin-centric therapeutics, including receptor agonists and lifestyle interventions, for metabolically-defined subgroups of MDD.</p> Graphical Abstract <p></p>