Objective: This study aimed to investigate the potential effects of the combination therapy of irsogladine maleate (IM) and azithromycin (AZM) on the inflammation in lipopolysaccharide (LPS)-induced gingival epithelial cells. Methods: Human gingival epithelial cell OBA-9 was stimulated by LPS to construct the periodontitis model, followed by the treatment of irsogladine maleate (IM) or azithromycin (AZM) with different concentration. Trans epithelial electrical resistance (TER) of cells in each group was analyzed, and qRT-PCR and western blotting were used to detect the expressions of inflammatory cytokines. Immunofluorescence staining was performed to detect the protein expression. Results: The TER for cells was significantly decreased while the inflammatory cytokines expressions including IL-6, IL-8, IL-beta and TNF-alpha were all significantly increased by LPS compared to the control (P<0.05). However, TER was increased significantly, whereas the cytokine levels were decreased by IM or AZM, but these effects was more apparent in cells treated with IM and AZM combination (P<0.01). Moreover, E-cadherin and vimentin expressions were more positive in the IM and AZM group than in the other groups. The application of ERK and P38 MAPK inhibitors reversed the effects of LPS on cell inflammatory cytokine production and cell TER. Conclusion: This study revealed that the combination therapy of IM and AZM performed excellent effects on preventing the inflammatory progression of periodontitis.