Rationale <p>Major depressive disorder (MDD) is a significant global health issue, yet its pathophysiology remains unclear. One-third of patients achieve complete remission with monotherapy, highlighting the need for effective add-on therapies.</p> Objectives <p>This study explores the antidepressant potential of galantamine (GAL) as an add-on to escitalopram (ESC), focusing on the neurotrophic system, kynurenine pathway, neuroinflammation, and oxidative stress in MDD.</p> Methods <p>We employed corticosterone (CORT)-induced toxicity in Neuro-2a cells and an unpredictable chronic mild stress (UCMS) model in mice to simulate depressive conditions. Neuro-2a cells were treated with GAL (39 µM) and ESC (107 µM) in CORT pretreated cells to better understand the protective potential of the drug combination. In vivo treatment with GAL (3 and 5&#xa0;mg/kg) and ESC (5 and 10&#xa0;mg/kg) for four weeks in UCMS mice was evaluated for behavioural, biochemical, and histopathological changes.</p> Results <p>The combination therapy enhanced cell viability, reduced apoptosis, and lowered intracellular ROS levels in Neuro-2a cells. In vivo, treatment with the GAL + ESC combination significantly alleviated UCMS-induced depressive symptoms and improved working memory. The combined therapy modulated the brain-derived neurotrophic factor (BDNF), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), TNF-α, and IL-6 levels, reversing oxidative stress markers in the hippocampus. Moreover, the combined therapy preserved hippocampal structure and modulated α7 nicotinic acetylcholine receptor (α7nAChR) density in the CA1 region of the hippocampus.</p> Conclusions <p>This study signifies the potential of GAL as an add-on therapy to ESC, enhancing antidepressant effects and cognitive function, warranting further clinical investigation for treating depressive disorders.</p> Graphical Abstract <p></p>