Transforming growth factor beta (TGF-|β) signaling has pleiotropic functions controlling cancer initiation, development, and metastasis, as well as plays important roles within the interaction between stromal and cancer cells, making the path a possible therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-|β receptor I (TGFBRI), was examined for being able to hinder ovarian cancer (OC) growth in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to review the result of LY treatment on expression of cancer- and fibroblast-derived genes. Results demonstrated that contact with TGF-|β1 caused phosphorylation of SMAD2 and SMAD3 in most tested OC cell lines, however this induction was covered up by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-|β1-caused fibroblast activation was blocked by LY. LY also delayed tumor growth and covered up ascites formation in vivo. Additionally, separate from tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft examples we confirmed the inhibitory aftereffect of LY on TGF-|? signaling and tumor stromal expression of bovine collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations advise a role for anti-TGF-|β signaling-directed therapy in ovarian cancer.