The thrombospondins (TSPs), multifunctional matricellular proteins, are known mediators of endothelial cell (EC) angiogenesis and apoptosis. TSP‐1, an antiangiogenic molecule, is important in the progression of vascular disease, in part by inducing EC apoptosis. TSP‐2, although less studied, also induces EC apoptosis and inhibits angiogenesis. The effects of TSP‐5 are largely unexplored in ECs, but TSP‐5 is believed to be protective against arterial disease. Statin drugs have been shown to have beneficial pleiotropic effects, including decreasing EC apoptosis, increasing angiogenesis, and blocking TSP signaling. We hypothesized TSP‐5 will be proangiogenic and antiapoptotic, and statin pretreatment would reverse the proapoptotic and antiangiogenic phenotype of TSP‐1 and TSP‐2. ECs were exposed to serum‐free medium, TSP‐1, TSP‐2, or TSP‐5 with or without fluvastatin pretreatment. Quantitative real‐time polymerase chain reaction was performed on 96 apoptosis and 96 angiogenesis‐related genes using microfluidic card assays. Angiogenesis was measured using Matrigel assays, while apoptosis was measured by fluorescent caspase assay. TSP‐5 suppressed apoptotic genes and had a mixed effect on the angiogenic genes; however, TSP‐5 did not alter apoptois but was proangiogenic. Pretreatment with fluvastatin downregulated proapoptotic genes and apoptosis and upregulated proangiogenic genes and angiogenesis. Findings indicate TSP‐5 and fluvastatin have a protective effect on ECs, being proangiogenic and reversing the antiangiogenic effects of TSP‐1 and TSP‐2. In conclusion, TSP‐5 and fluvastatin may be beneficial for inducing angiogenesis in the setting of ischemia.