Depressive disorders are the leading cause of the neuropsychiatric disparity, and the lack of understanding of the causes and treatment of these disorders progresses toward therapeutic failure. Current treatment approaches only provide symptomatic relief but fail to cure the underlying pathophysiology. The present study aimed to investigate the antidepressant effect of escitalopram (ESC) and galantamine (GAL) combination in vivo on a chronic unpredictable mild stress (CUMS)-induced depression in mice and further explored its mechanism of action around cAMP, BDNF-related neurotrophic signaling, and alpha-7 nicotinic receptor (α7nAChR). Our findings demonstrated that CUMS for seven weeks caused a significant decline in the neurobehavioral parameters, including elevation in immobility time in the forced swimming test, tail suspension test, entries in the closed arm in the elevated plus maze test, and reduced mobility around the central arena of the open field test, indicating the typical depressive behavior and successful development of the model. However, the combination of ESC (5 and 10 mg/kg) and GAL (3, 5 mg/kg) distinctly reversed the above indicators, exhibiting antidepressant potential. Additionally, combination treatment upregulated the BDNF and cAMP expression, downregulated neuroinflammatory cytokines, and sustained the structural integrity of α7nAChR in the hippocampal region. Overall, the study signifies the immense potential of the combination for its antidepressant activity with improved cognition in CUMS-induced depression and warrants the clinical translation to treat cognitive disorders.