Nanostructured biomaterials have great potential in the field of biomedical engineering. Efforts for treatment of cardiovascular diseases focused on introducing vascular substitutes that are nonthrombogenic and have long‐term patency, but still there is not any perfect replacement for clinical use. In this study, nanostructure tubes of a commonly known biocompatible polymer, polyethylene terephthalate (PET), were prepared via electrospinning process using small diameter mandrel as a collector with two different speeds. The nanofibers (NFs) morphologies' physical and mechanical properties were investigated according to scanning electron microscope (SEM), water contact angle (WCA), porosity measurement, differential scanning calorimetry (DSC), and tensile test. Finer NFs, more percentage of crystallinity, and superior mechanical properties were observed for samples prepared by higher speed mandrel. Since both samples stimulated platelet adhesion and activation, further surface modification with sodium nitrate as nitric oxide (NO) donor was done using two different approaches: dip‐coating and electrospraying. The modified NFs were evaluated via SEM, WCA, tensile test, platelets, and cell adhesion. The results showed more hydrophilicity, reduction in platelet adhesion, and improved blood compatibility for eNO‐HS (electrosprayed NO for higher collector speed) compared with other samples implying the promising potential of this fabrication and modification technique for improving PET‐based cardiovascular substitutes.