<p>Social defeat stress induces behaviors associated with both depression and anxiety in animals, but the mechanisms involved remain inadequately understood. This study aimed to examine the effects of social defeat stress on anxiety-related behaviors and cognitive impairments <i>via</i> the activation of the endoplasmic reticulum stress (ER stress)-nuclear factor kappa-B (NF-κB)-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathway in adult mice.&#xa0;Adult mice were assigned to four groups: control, social defeat stress, social defeat stress + phenylbutyric acid (PBA), and tunicamycin (TM). Mice in the social defeat stress and social defeat stress + PBA groups underwent a 10-day social defeat protocol, while the TM group received a 2&#xa0;mg/kg intraperitoneal injection of TM. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were measured using ELISA. Behavioral assessments were followed by Western blotting and immunofluorescence staining to evaluate changes in the ER stress-NLRP3 pathway in the medial prefrontal cortex (mPFC).&#xa0;Social defeat stress induced anxiety-like and depression-like behaviors and impaired memory function in all stressed mice. It also increased the expression of ER stress markers, activated NF-κB, and triggered the NLRP3 inflammasome. The ER stress inhibitor PBA alleviated these effects.&#xa0;The results indicate that social defeat stress induces anxiety-like, depression-like behaviors, and cognitive dysfunction in mice, with the activation of the ER stress-NF-κB-NLRP3 pathway in the mPFC playing a critical role in these outcomes. Inhibition of ER stress reduced NLRP3 inflammasome expression <i>via</i> NF-κB, thereby mitigating cognitive deficits and improving anxiety-and depression-like behaviors.</p> Graphical abstract <p></p>