To investigate the relationship between the anti-proliferation effect of baicalein and extracellular signal-regulated kinase and focal adhesion kinase(ERK-FAK) signal pathway in oral squamous cell carcinoma (OSCC). The study included two parts and each part contained 4 groups, including control, 20 μmol/L BAI, 40 μmol/L BAI, 80 μmol/L BAI or control, 40 μmol/L BAI, MEK inhibitor(0.33 nmol/L),MEK inhibitor(0.33 nmol/L)+40 μmol/L BAI.Each group was treated in triplicate for 24 hours and 48 hours.Cell counting kit-8 (CCK8) was used to detect the inhibitory effect of baicalein; Polymerase chain reaction(PCR) and Western blot were used to analysis the effect of Baicalein on E-cadherin and Vimentin. The expressions of extracellular signal-regulated kinase(ERK), phosphorylated (p-ERK), focal adhesion kinase (FAK) and phosphorylated focal adhesion kinase(p-FAK) were detected by Western blot. The regulatory effect of MEK inhibitor(U0126) on Baicalein was tested by Western blot assay. The survival rate of cells treated with BAI is much lower than that of control group(P<0.01); the mRNA and protein levels of E-cadherin were obviously higher than those of control group, while the mRNA and protein levels of Vimentin were lower than those of control group(P<0.01).The protein levels of p-ERK and p-FAK treated with BAI were much lower than those of control group(P<0.01), but the total ERK and FAK had no obvious changes (P<0.05).The protein level of E-cadherin treated with MEK inhibitor was higher than that of control group(P<0.01) and the protein levels of Vimentin, p-ERK and p-FAK were lower than those of control group (P<0.01), while the total protein levels of ERK and FAK were the same(P<0.05). Baicalein can inhibit the proliferation and invasiveness of OSCC, which may be mediated by ERK-FAK signal pathway.