Poly(2-methoxyethyl acrylate) (PMEA) is a US FDA-approved biocompatible polymer, although there is insufficient work on human umbilical vein endothelial cells (HUVECs) and platelet interaction analysis on PMEA-analogous polymers. In this study, we extensively investigated HUVEC–polymer and platelet–polymer interaction behavior by measuring the adhesion strength using single-cell force spectroscopy. Furthermore, the hydration layer of the polymer interface was observed using frequency-modulation atomic force microscopy. We found that endothelial cells can attach and spread on the PMEA surface with strong adhesion strength compared to other analogous polymers. We found that the hydration layers on the PMEA-analogous polymers were closely related to their weak platelet adhesion behavior. Based on our results, it can be concluded that PMEA is a promising candidate for the construction of artificial small-diameter blood vessels owing to the presence of IW and a hydration layer on the interface.