Rationale <p>Psychiatric disorders are a largely elusive aspect of obesity, representing a growing public health concern. In this regard, a large body of evidence indicates a pivotal role of disturbed autophagic flux in the pathogenesis of obesity-associated neuropsychiatric deficits.</p> Objectives <p>This work was designed to evaluate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, which is increasingly utilized for the management of chronic obesity, on the depressive/cognitive deficits in the high-fat diet (HFD) rat model of obesity with an emphasis on its hippocampal mechanistic backgrounds.</p> Methods <p>The effects of chronic liraglutide administration (subcutaneous; 300&#xa0;µg/kg/day for 28 days) were investigated on depressive-like phenotypes, cognitive deficits, and hippocampal phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)-regulated autophagy.</p> Results <p>Chronic liraglutide treatment amended the HFD-induced depressive-like phenotype (in the sucrose preference and the forced swimming tests) and cognitive deficits (in the Morris water maze test). Moreover, liraglutide enhanced the hippocampal expression of brain-derived neurotrophic factor (BDNF), PI3K, Akt, p-Akt, and p-mTOR and downregulated the expression of the autophagic markers (Beclin-1, LC3) and the inflammatory markers (TNF-α, IL-6) with amelioration of HFD-induced hippocampal neurodegeneration.</p> Conclusions <p>This work highlights the antidepressant and pro-cognitive properties of liraglutide in HFD-exposed rats, which could be mediated through amelioration of the disrupted PI3K/Akt/mTOR signaling activity with a possible impedance of the exaggerated autophagy-mediated neurodegenerative cascades. Indeed, this study highlights that liraglutide is not only effective in weight control, but its effects also extend to managing obesity-related psychiatric disorders.</p>