Trophoblast invasion is an important event in embryo implantation and placental development. During these processes, endocrine gland‐derived vascular endothelial growth factor (EG‐VEGF) is the key regulator mediating the crosstalk at the feto‐maternal interface. The primary cilium is a cellular antenna receiving environmental signals and is crucial for proper development. However, little is known regarding the role of the primary cilium in early human pregnancy. Here, we demonstrate that EG‐VEGF regulates trophoblast cell invasion via primary cilia. We found that EG‐VEGF activated ERK1/2 signaling and subsequent upregulation of MMP2 and MMP9, thereby facilitating cell invasion in human trophoblast HTR‐8/SVneo cells. Inhibition of ERK1/2 alleviated the expression of MMPs and trophoblast cell invasion after EG‐VEGF treatment. In addition, primary cilia were observed in all the trophoblast cell lines tested and, more importantly, in human first‐trimester placental tissue. The receptor of EG‐VEGF, PROKR1, was detected in primary cilia. Depletion of IFT88, the intraflagellar transporter required for ciliogenesis, inhibited primary cilium growth, thereby ameliorating ERK1/2 activation, MMP upregulation, and trophoblast cell invasion promoted by EG‐VEGF. These findings demonstrate a novel function of primary cilia in controlling EG‐VEGF‐regulated trophoblast invasion and reveal the underlying molecular mechanism. J. Cell. Physiol. 232: 1467–1477, 2017. © 2016 Wiley Periodicals, Inc. Primary cilium is a cellular antenna that conveys extracellular signals into a cellular response. EG‐VEGF binds to PROKR1 locating on the cilium, and activates ERK1/2 signaling followed by upregulating MMP2 and MMP9 for facilitating cell invasion. We demonstrated that EG‐VEGF regulated trophoblast cell invasion via primary cilium in the present study.