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Objective: Adequate extravillous trophoblast (EVT) invasion plays a crucial role in the establishment of successful pregnancy. Insufficient trophoblast migration and invasion can result in defective placentation, which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation. Methods: We utilized immortalized human first-trimester EVT cells (HTR8/SVneo) for our functional study. We examined the effects of Gal-9 on viability, proliferation, and invasion of HTR8/SVneo cells, as well as on matrix metalloproteinase-2 (MMP-2) production in HTR8/SVneo cells. Furthermore, we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells' invasion. Results: We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion. Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3, not CD44, and subsequently increased MMP-2 production. Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells. Conclusion: Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.