Introduction Obesity and depressive disorders are among the most prevalent chronic conditions worldwide. Increasing evidence suggests a bidirectional relationship between obesity and depression. Their coexistence is associated with a higher risk of metabolic diseases, poorer clinical outcomes, and reduced quality of life. In recent years, growing attention has been focused on the biological mechanisms underlying this association. Methods A narrative review of the literature was conducted using the PubMed and Scopus databases. The search included publications published between 2011 and 2025. Clinical studies, systematic reviews, and meta-analyses addressing the biological mechanisms linking obesity and depression were included. Results Available evidence indicates that obesity increases the risk of developing depression, while depression may contribute to weight gain through lifestyle changes and neuroendocrine disturbances. The key biological mechanisms include chronic lowgrade inflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, alterations in neurotransmitter systems, and changes in the gut–brain axis associated with the gut microbiota.