Objective To investigate the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) in modulating the cGAS-STING-NF-κB signaling pathway in chronic intermittent hypoxia (CIH) mice. Methods Twenty-four C57BL/6 mice were divided into the control group, the model group, the hUCMSCs group and the hUCMSCs+STING agonist (DMXAA) group, with 6 mice in each group. Except for the control group, the other groups were exposed to hypoxic conditions for 8 hours daily for a total of 8 weeks to establish the CIH mouse model. After 8 weeks, mice were anesthetized for cardiac blood collection followed by euthanasia and lung tissue collection. Serum levels of IL-6, TNF-α, IL-1β and IL-17A were measured by ELISA. Pulmonary inflammatory infiltration and collagen deposition were assessed by HE and Masson staining. E-Cadherin and α-SMA expression levels were evaluated by immunohistochemistry. Expression levels of cGAS, STING and NF-κB mRNA were detected by RT-qPCR, while protein expression levels of E-Cadherin, N-Cadherin, α-SMA, Vimentin, cGAS, STING and NF-κB were analyzed by Western blot assay. Results Compared with the control group, levels of IL-6, IL-1β, TNF-α and IL-17A increased in the model group, inflammation and fibrosis scores increased, mRNA expression levels of cGAS, STING and NF-κB increased, and protein expression levels of N-Cadherin, α-SMA, Vimentin, cGAS, STING and NF-κB increased. In contrast, E-Cadherin protein expression was significantly decreased (P<0.05). Compared with the model group, IL-6, IL-1β, TNF-α and IL-17A decreased in the hUCMSCs group, mRNA expression levels of cGAS, STING and NF-κB were decreased, protein expression levels of N-Cadherin, α-SMA, Vimentin, cGAS, STING and NF-κB were also decreased. Meanwhile, E-Cadherin protein expression was significantly increased (P<0.05). STING activator DMXAA reversed the protective effects of hUCMSCs in CIH mice (P<0.05). Conclusion Intravenous administration of hUCMSCs alleviates pulmonary inflammatory infiltration and epithelial-mesenchymal transition in mouse model of intermittent hypoxia, which may be related to the down-regulation of the cGAS-STING-NF-κBsignaling pathway.