The present invention provides a bi-functional fusion protein, (AT)a-Fc-(VT)b, simultaneously targeting vascular endothelial growth factor (VEGF) and angiopoietins (ANGs), wherein AT is an ANG binding motif; and VT is a VEGF binding motif, Fragment crystallizable region (Fc) is an N-terminal of Immunoglobulin G (IgG); each of a and b is an integer from 1 to 10. The bi-functional fusion proteins contain two or more domains of human proteins and are of all human sequences, and thus are expected to be non-immunogenic, and potentially can be used therapeutically in human targeting angiogenesis-associated diseases.