This study explored the following: (1) downregulation of EGFL7 did not affect the proliferation and apoptosis of human osteosarcoma cell line U2OS; (2) it also did not affect the proliferation and apoptosis of HUVEC; (3) the in vitro co-culture transwell system was used for simulating the interaction between two cells in vivo, and the inhibited EGFL7 in U2OS was able to significantly reduce the migration, adhesion, and angiogenesis of HUVEC; (4) combined with these functional changes, the expression levels of PI3K, p-Akt, and VEGF decreased. This evidence concerns the gene VEGFA and osteosarcoma.