AIMS: Depression is prevalent in inflammatory bowel disease (IBD) and linked to neuroinflammation. However, the underlying mechanisms remain unclear. Therefore, we investigated the efficacy of electroacupuncture in mice with IBD and depression. METHODS: An IBD mouse model of depression was established using 2.0% dextran sodium sulfate (DSS). After electroacupuncture, general condition and behavior were evaluated. Colon morphology was observed using hematoxylin and eosin staining. Serum inflammatory factors were detected using enzyme-linked immunosorbent assay. Microglial activation was measured using immunofluorescence. Hippocampal protein expression was assessed using Western blotting and real-time fluorescence quantitative polymerase chain reaction. RESULTS: DSS-induced model mice exhibited significant depression-like behaviors and colon pathology. Serum and colon IL-1β expression was elevated (p < 0.01), while IL-4, IL-10, and TGF-β1 expression was decreased (p < 0.01 or p < 0.05). Hippocampal microglial activation was evident, with increased IL-1β expression (p < 0.01) and reduced IL-4, IL-10, TGF-β1, JAK1, STAT6, and p-STAT6 expression (p < 0.01 or p < 0.05). Electroacupuncture resolved these changes; though its effects were significantly weakened after IL-4 and p-STAT6 inhibitor administration (p < 0.01 or p < 0.05). Transcriptomic sequencing of hippocampal tissue indicates that pro-inflammatory pathways such as TNF/NF-κB/mTOR are activated in the model group. Electroacupuncture can activate the IL-4-mediated JAK-STAT signaling pathway, inhibit the activation of pro-inflammatory signaling pathways, upregulate neuroprotective genes such as Slc2a3, Mef2d, and Jak1, and exert anti-inflammatory effects. CONCLUSION: IL-4-JAK1-STAT6 signaling may be an important pathway in mediating the efficacy of electroacupuncture in IBD with comorbid depression, particularly promoting microglial M2 polarization and improving neuroinflammation.