<p>Major depressive disorder (MDD) is a highly disabling mental disorder, and its complex etiology remains elusive. Recent studies have shown that there is a close bidirectional relationship between metabolic disorders and MDD. Metabolic pathway disorders are not simply comorbid phenomena but may be deeply involved in the pathophysiological process of MDD. This review provides a systematic evaluation of metabolic dysregulations in MDD, encompassing amino acid, glucose, and lipid pathways. Distinct from existing literature that often treats these systems in isolation, our work uniquely highlights the synergistic integration of mitochondrial and endoplasmic reticulum (ER) dysfunction with the neuroinflammatory cascade. Specifically, we propose a multidimensional “organelle-immune-metabolic” framework to elucidate how cellular stress and systemic inflammation reinforce each other to drive MDD pathogenesis. Ultimately, this in-depth exploration not only advances the mechanistic understanding of MDD but also establishes a critical foundation for developing targeted, metabolism-based precision therapeutics.</p>