Objective: This study aims to elucidate the underlying mechanism by which microRNA (miR)-146a-5p and its target gene, autophagy related gene 7 (ATG7), affect the inflammatory response and vascular permeability via the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway in chronic idiopathic urticaria (CIU). Methods: 46 patients with CIU were included in this study. An autologous serum skin test and a serum immunoglobulin assay were performed. Expression of ATG7 in skin tissue was measured by immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect the levels of serum inflammatory factors. Dual luciferase reporter assay was used to confirm whether ATG7 was a target gene of miR-146a-5p. Mast cells and human dermal capillary endothelial cells were prepared and divided into six groups: blank, negative control (NC), miR-146a-5p mimic, miR-146a-5p inhibitor, small interfering (si)RNA-ATG7 and miR-146a-5p mimic + siRNA-ATG7. qRT-PCR and western blotting were used to measure relative gene and protein expression levels, respectively. The mast cell degranulation was calculated. The histamine release rate and vascular permeability were also measured. Results: The results demonstrated that, compared with the Control group, the wheal diameter and the expression of ATG7, immunoglobulin (10, levels of C5a, C3 and C4, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cell count (WBC), rheumatoid factor (RF), IL-4, IL-10 and IgE were significantly increased in patients with CIU, and the JAK/STAT3 pathway was activated. However, the expression levels of IgG, IgM, interferon-alpha (IFN-alpha) and miR-146a-5p were significantly downregulated in patients with CIU compared with control patients. Luciferase assay confirmed that ATG7 was the target gene of miR-146a-5p. Compared with the blank group, cells transfected with miR-146a-5p mimic, siRNA-ATG7 and miR-146a-5p mimic + siRNA-ATG7 showed a lower rate of degranulation, histamine release and skin vascular permeability, and activation of the JAK/STAT3 pathway was inhibited. Conversely, the inhibition of miR-146a-5p was able to promote mast-cell degranulation and release of histamine, skin vascular permeability and JAK/STAT3 pathway activation. Conclusion: The present study demonstrated that miR-146a-5p could alleviate the inflammatory response and vascular permeability through inhibition of the JAK/STAT3 signaling pathway by targeting ATG7 in CIU. These results suggested that miR-146a-5p may be a potential diagnostic marker and therapeutic target for CIU.