Objective To explore the role and related mechanism of miR-155-5p in Sjogren's syndrome. Methods Mice were randomly divided into normal control group, model group, miR-155-5p knockdown group (anti-miR-155-5p), and knockdown control group (anti-miR-NC), with 9 mice in each group. Mice in anti-miR-155-5p group and anti-miR-NC group were injected with knockdown miR-155-5p and its control lentivirus via tail vein injection, respectively. After 4 weeks of injection, the water intake and saliva flow rate of the mice were measured. RT-qPCR was used to detect miR-155-5p, suppressor of cytokine signaling 1 (SOCS1), and nuclear factor κB p65 (NF-κB p65) mRNA levels in submandibular gland. Western blot was used to detect SOCS1, NF-κB p65, and p-NF-κB p65 protein levels in submandibular gland. ELISA was used to detect interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-4, and IL-10 levels in serum. HE staining was used to observe the pathological damage of submandibular gland. SGECs cells were divided into Control group, interferon-γ group (IFN-γ), miR-155-5p knockdown group (anti-miR-155-5p), knockdown control group (anti-miR-NC), overexpression SOCS1 group (SOCS1), overexpression control group (NC), overexpression miR-155-5p + overexpression SOCS1 group (miR-155-5p+SOCS1), and overexpression control + overexpression SOCS1 group (miR-NC+SOCS1). Cells in Control group and IFN-γ group were cultured routinely, while cells in other groups were infected with corresponding lentiviruses carrying knockdown/overexpression and control genes. After screening, Cells in Control group were cultured routinely for 24 h. Cells in other groups were cultured in medium containing 10 ng/mL IFN-γ for 24 h. RT-qPCR was used to detect miR-155-5p, SOCS1, and NF-κB p65 mRNA levels in cells; Western blot was used to detect SOCS1, NF-κB p65, p-NF-κB p65, Ki67, PCNA, Bcl-2, and Bax protein levels in cells. Target scan database prediction and dual luciferase assay were used to validate the targeted regulation of SOCS1 by miR-155-5p. CCK-8 experiment was used to detect cell survival rate; Annexin V-FITC/PI staining was used to detect cell apoptosis rate; ELISA was used to detect IL-1β, TNF-α, IL-4, and IL-10 levels in cell culture supernatant. Results Compared with Control group, water intake in Model group was increased, and saliva flow rate was decreased, miR-155-5p and NF-κB p65 mRNA and protein levels in submandibular gland were increased, SOCS1 mRNA and protein levels were decreased, pathological damage of submandibular gland was obvious, IL-1β and TNF-α levels in serum was increased, IL-4 and IL-10 levels were decreased (P＜0.05). Compared with anti-miR-NC group, water intake in anti-miR-155-5p group was decreased, and saliva flow rate was increased, miR-155-5p and NF-κB p65 mRNA and protein levels in submandibular gland were decreased, SOCS1 mRNA and protein levels were increased, pathological damage of submandibular gland was reduced, IL-1β and TNF-α levels in serum were decreased, IL-4 and IL-10 levels were increased (P＜0.05). Compared with Control group, miR-155-5p and NF-κB p65 mRNA and protein levels of cell in IFN-γ group were increased, SOCS1 mRNA and protein levels were decreased, cell survival rate was decreased, cell apoptosis rate was increased, Ki67, PCNA, Bcl-2 protein levels in cell were decreased, Bax protein levels was increased, IL-1β and TNF-α levels in cell culture supernatant were increased, IL-4 and IL-10 levels were decreased (P＜0.05). Compared with anti-miR-NC group /NC group, miR-155-5p and NF-κB p65 mRNA and protein levels of cell in anti-miR-155-5p group /SOCS1 group were decreased, SOCS1 mRNA and protein levels were increased, cell survival rate was increased, cell apoptosis rate was decreased, Ki67, PCNA, Bcl-2 protein levels in cell were increased, Bax protein levels was decreased, IL-1β and TNF-α levels in cell culture supernatant were decreased, IL-4 and IL-10 levels were increased (P＜0.05); MiR-155-5p targeted SOCS1. Overexpression of miR-155-5p could reduce the effect of overexpression of SOCS1 on the above indicators (P＜0.05). Conclusion miR-155-5p promotes submandibular gland inflammation and cell apoptosis by targeting SOCS1/NF-κB pathway, and miR-155-5p may be a potential target for the treatment of Sjogren's syndrome