Periodontal diseases often begin with chronic gingival inflammation, which causes the destruction of periodontal tissues. Inflammatory immune responses from host cells to bacteria, such as Porphyromonas gingivalis (P. gingivalis), cause periodontal degradation. Human gingival fibroblasts (HGFs) are the major cells in periodontal soft tissues. When stimulated by lipopolysaccharide (LPS), HGFs could secrete several pro-inflammatory cytokines and chemokines, such as interleukins (ILs) IL-6, IL-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2). Caffeic acid phenethyl ester (CAPE) is the main active component of propolis, which is collected by honeybees from different plants and known for its anti-inflammatory effects. The anti-inflammatory effects of CAPE on the LPS-induced HGFs were demonstrated in this study. HGFs were pretreated with CAPE (10, 20, and 30µm) for 1h, followed by LPS stimulation (1μg/ml) for 24h. Enzyme-linked immunosorbent assay, Western blot analysis, and immunofluorescence staining were used to evaluate the production of IL-6, IL-8, iNOS, and COX-2, as well as the activation of TLR4-mediated NF-κB, PI3K/AKT, and MAPK signaling pathways. The results indicated that CAPE inhibits LPS-induced IL-6, IL-8, iNOS, and COX-2 production in a dose-dependent manner. Moreover, CAPE suppresses LPS-induced TLR4/MyD88 and nuclear factor kappa B (NF-κB) activation. In addition, phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) phosphorylation was inhibited by CAPE. These results demonstrated that CAPE could be effective for treating of periodontal diseases.