The aim of this study was to investigate the effect of suppressor of cytokine signaling 3 (SOCS3) on the  high glucose(HG)-induced inflammatory factors expression in rat glomerular mesangial cell (RMC) and the related mechanism. For this purpose, RMCs were divided into six groups: normal control (NC) group, osmotic control (OSM) group, HG group, HG+TAK-242 (TLR4 inhibitor) group, HG+sh-SOCS3 group, and HG+sh-SOCS3+TAK-242 group. Cell viability was detected by CCK-8 assay and cell apoptosis was detected by FACS. The levels of inflammatory factors TNF-α, IL-1β, IL-6, and COX2 in cell culture supernatant were detected by ELISA. The mRNA expressions of TLR4, NF-κB p65, and IκB-α in RMC were detected by qPCR. The protein expressions of TLR4, NF-κB p65, p-p65, IκB-α, and p-IκB-α were detected by western blotting. The results showed that compared to those of  NC group, the cell survival rate of the HG group was significantly decreased (P＜0.01), while the cell apoptosis rate, the levels of TNF-α, IL-1β, IL-6 and COX2 in cell culture supernatant, the mRNA expression of TLR4, p65 and IκB-α and the protein expression of TLR4、p-p65 and p-IκB-α were significantly increased (all with P＜0.01). Compared to those of  HG group, the cell survival rates of the HG+TAK-242 group and the HG+sh-SOCS3 group were significantly increased (both P＜0.05) while the apoptosis rate, the levels of TNF-α, IL-1β, IL-6 and COX2 in the cell culture supernatant, the mRNA expression of TLR4, p65, and IκB-α, and the protein expression of TLR4, p-p65, and p-IκB-α were significantly decreased (all with P＜0.05). The above changes were more significant in the HG+sh-SOCS3+TAK-242 group than the HG+TAK-242 group (all with P＜0.05). Taken together, SOCS3 up-regulates the expression of inflammatory factors in RMCs cultured with HG by activating the TLR4/NF-κB signaling pathway, thus aggravates the inflammatory responses.