Hydrophilic thermoplastic polyurethane (TPU) is applicable in the fields of packaging, oil–water separation, and biomedical. Nevertheless, the process of its preparation is still a great challenge. The objective of this study is to develop TPU with excellent wettability and hydrophilic stability by surface modification. Four methods were evaluated: coating with PVP (polyvinylpyrrolidone) solution, immersion in PVP solution, N2/Ar plasma treatment, and N2/Ar plasma-induced graft polymerization with PVP. Finally, the results indicate that the sample called TPU-g-PVP, which utilizes plasma-induced grafting, exhibits the best performance. The water contact angle (WCA) reduces from 109° to 9.2°, and maintains within 20° after 80 days under atmospheric conditions. Its surface energy (72.4 mN/m) is increased by 2.8 times than untreated TPU. The surface morphology and roughness are almost unchanged when compared to the original TPU. Some characteristic peaks (–OH and C = O) of PVP on the TPU-g-PVP were found by infrared spectroscopy. X-ray photoelectron spectroscopy (XPS) examination revealed a reduction in C on the TPU surface as the content of N and O increases. Experiments on biocompatibility showed that the PVP deposited substrates improved cell adherence without generating new cytotoxicity.