Background <p>Chronic obstructive pulmonary disease (COPD) and depression frequently co-occur, yet the biological basis of this comorbidity and effective therapeutic strategies remain poorly defined.</p> Methods <p>We established a rat model of COPD-depression comorbidity through sequential cigarette-smoke exposure and chronic unpredictable mild stress. Pulmonary function, depression-like behaviors, histopathology, and MAPK/NF-κB signaling in lung and hippocampus were assessed. Esketamine or esketamine plus the TLR1/2 agonist Diprovocim was administered for 14 days. Cytokines, oxidative-stress markers, neuronal apoptosis, and microglial activation were evaluated. Complementary in-vitro studies used NR8383 alveolar macrophages (CSE model) and HAPI microglia (LPS + CSE). Gut and lung microbiota were profiled by 16&#xa0;S rRNA sequencing and correlated with physiological and inflammatory indices.</p> Results <p>Comorbid rats displayed airflow limitation, depression-like behaviors, systemic inflammation, oxidative stress, and MAPK/NF-κB activation. Esketamine improved pulmonary function and behavior, reduced neuronal apoptosis and microglial activation, and suppressed MAPK/NF-κB signaling; these effects were partly reversed by Diprovocim. In vitro, esketamine increased macrophage and microglial viability, lowered proinflammatory cytokines and oxidative markers, and inhibited pathway activation. Microbiota profiling showed dysbiosis of gut and lung communities, with loss of beneficial taxa and expansion of conditional pathogens, whereas esketamine partially restored balance by promoting commensals and reducing potential pathogens.</p> Conclusions <p>These findings delineate a gut-lung-brain inflammatory-microbial network in COPD-depression comorbidity and identify esketamine as a multi-target intervention capable of modulating signaling pathways, inflammation and oxidative stress, and microbial homeostasis.</p> Graphical Abstract <p></p>