Semaphorins, the neuronal guidance cues, were shown to have broad influences on pathophysiological processes such as bone remodeling, immune responses, and angiogenesis. In particular, Class-3 Semaphorins (SEMA3) is considered a vital regulator involved in angiogenesis. Scientific evidence has pointed to the role of angiogenesis in many diseases, and numerous efforts have been made to explore the possibilities of curing those diseases by targeting angiogenesis. Nevertheless, the efficacies are limited owing to the complex mechanisms of angiogenesis. Hence, investigating the mechanisms of SEMA3 in angiogenesis may contribute to novel therapeutics for diseases. Previous reviews mainly focused on the various functions of semaphorins in one particular disease, and the specific angiogenesis mechanism of SEMA3 in diverse diseases has not been well elucidated. Additionally, the role of SEMA3 in angiogenesis remains elusive, as contradicting results have been found in different disease types. Some evidence from recent studies implies that, while most SEMA3 molecules inhibit pathological angiogenesis in different diseases, occasionally SEMA3 may also promote angiogenesis. This review summarizes the specific role of SEMA3 in a variety of angiogenesis-associated diseases, and documents SEMA3 may be a promising therapeutic target for treating angiogenesis-associated diseases.