Ovarian cancer is one of the most common gynecologic cancers and the leading cause of mortality in women worldwide. HER2/neu is overexpressed in various types of cancers and is most commonly associated with decreased survival. Trastuzumab is a humanized anti-HER2 monoclonal antibody for the treatment of HER2-positive breast cancers. However, primary and/or acquired resistance occurs in up to 62% patients during the first year of treatment. Vascular endothelial growth factor (VEGF) is a well‑known angiogenesis factor involved in many physiological and pathological processes. Its significance has been implicated in promoting tumor growth and metastasis via angiogenesis. In the present study, we demonstrated that the upregulation of SP1 enhanced expression of VEGF promoting the angiogenesis and migration of trastuzumab-resistant ovarian cancer cell line SKOV3-T. Our in vitro and in vivo results both gave evidence that the SP1-VEGF axis was responsible for the enhanced malignancy, angiogenesis and migration in the acquired trastuzumab-resistant ovarian cancer cell model.