Embryonic development depends on the normal invasion of trophoblast cells. Forkhead box C2 (FOXC2) is a member of Forkhead box family, which is involved in the tumor cells invasion. The aim of this study was to explore the roles of FOXC2 on the invasion of human trophoblast cells, and further study its molecular mechanism. The mRNA and protein levels of FOXC2 in human normal trophoblast and choriocarcinoma cell lines were analyzed by quantitative real-time PCR (qRT-PCR) and Western blot assays, respectively. Methylthiazolyldiphenyl-tetrazo lium bromide (MTT) and transwell assays were separately performed to detect the adhesion and invasion of normal trophoblast cells treated with exogenous FOXC2 and FOXC2 siRNA. QRT-PCR and Western blot assays were used to test levels of the epithelial-mesenchymal transition (EMT)-related and Hedgehog (Hh) signaling pathway-related factors, respectively. Herein, our results found that the expression levels of FOXC2 in normal trophoblast cells were lower than choriocarcinoma cells. FOXC2 over-expression remarkably strengthened the adhesion and invasion abilities of normal trophoblast cells. Moreover, over-expression of FOXC2 significantly promoted the expression of human leukocyte antigen-G (HLA-G), matrix metalloproteinase-2 (MMP-2), Vimentin, sonic hedgehog (Shh), Glioma-associated oncogene homolog 1 (Gli1), and Snail, and inhibited E-cadherin expression. However, it showed the opposite tendency in FOXC2 siRNA group. In addition, there was no significant change in the expression of MMP9 among different groups. Above results illustrated that FOXC2 could promote the invasion ability of normal trophoblast cells by EMT-mediated Hh pathway.